Variant: NM_004958.3:c.3117+34G>A

CA590307

1276811 (ClinVar)

Gene: MTOR

Condition: overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

Inheritance Mode: Autosomal dominant inheritance (mosaic)

UUID: aaf4c962-622f-4aec-a00e-64b55b6f0798

Approved on: 2022-02-11

Published on: 2022-02-11

HGVS expressions

NM_004958.3:c.3117+34G>A
NC_000001.11:g.11216114C>T
CM000663.2:g.11216114C>T
NC_000001.10:g.11276171C>T
CM000663.1:g.11276171C>T
NC_000001.9:g.11198758C>T
NG_033239.1:g.51438G>A
ENST00000361445.9:c.3117+34G>A
ENST00000361445.8:c.3117+34G>A
NM_004958.4:c.3117+34G>A
NM_001386500.1:c.3117+34G>A
NM_001386501.1:c.1869+34G>A
NM_004958.4(MTOR):c.3117+34G>A

Benign

• Met criteria codes: BA1 BS2 BP7 BP4

• Not Met criteria codes: BS4 BS3 BS1 BP5 BP2 BP3 BP1 PS2 PS4 PS3 PS1 PP4 PP1 PP3 PP2 PVS1 PM6 PM2 PM3 PM1 PM4 PM5

Expert Panel

Brain Malformations VCEP

Criteria Specification Information

Evidence submitted by expert panel

Brain Malformations VCEP

This NM_004958.4(MTOR): c.3117+34G>A (p.=) variant is a synonymous (silent) variant that occurs at a nucleotide that is not conserved according to a PhyloP <0.1 (BP7). The results from in silico splicing predictors MaxEntScan, spliceAI and varSEAK support that this variant does not affect splicing (BP4). The highest population minor allele frequency in gnomAD v2.1.1 is 0.004847 in the South Asian population, which is higher than the ClinGen BMEP threshold ([>=0.00185]) for BA1, and therefore meets this criterion (BA1). This variant was identified the homozygous state in >3 individuals within control databases (BS2). In summary, this variant meets the criteria to be classified as Benign for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: BA1, BP4, BP7, BS2 ; -14 points (VCEP specifications version 1; Approved: 1/31/2021)

Met criteria codes

• BA1: 0.4847% in South Asian alleles in gnomAD
• BS2: 3 homozygotes
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No predicted effect on splicing per varSEAK, spliceAI and MaxEntScan.

Not Met criteria codes

• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline