Variant: NM_002524.5(NRAS):c.112-8A>G

CA292582

138538 (ClinVar)

Gene: NRAS

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: f78fdf60-318d-46a1-b4c9-1b3f963bb80a

Approved on: 2024-12-03

Published on: 2025-03-26

HGVS expressions

NM_002524.5:c.112-8A>G
NM_002524.5(NRAS):c.112-8A>G
NC_000001.11:g.114713986T>C
CM000663.2:g.114713986T>C
NC_000001.10:g.115256607T>C
CM000663.1:g.115256607T>C
NC_000001.9:g.115058130T>C
NG_007572.1:g.7909A>G
ENST00000369535.5:c.112-8A>G
ENST00000369535.4:c.112-8A>G
NM_002524.4:c.112-8A>G

Likely Benign

• Met criteria codes: BP7 BP4 BS1

• Not Met criteria codes: BA1 PP3 PM2

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specification: ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NRAS Version 2.3.0

Evidence submitted by expert panel

RASopathy VCEP

The NM_002524.5:c.112-8A>G variant is an intronic variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). The filtering allele frequency (the lower threshold of the 95% CI of 62/127294) of the c.112-8A>G variant in NRAS is 0.0003711 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen RASopathy VCEP threshold (≥0.00025) for BS1, and therefore meets this criterion (BS1). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BS1, BP4, BP7. (ClinGen RASopathy VCEP specifications version 2.3; 12/3/2024)

Met criteria codes

• BP7: The NM_002524.5:c.112-8A>G variant is an intronic variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7).
• BP4: The NM_002524.5:c.112-8A>G variant is an intronic variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7).
• BS1: The filtering allele frequency (the lower threshold of the 95% CI of 62/127294) of the c.112-8A>G variant in NRAS is 0.0003711 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen RASopathy VCEP threshold (≥0.00025) for BS1, and therefore meets this criterion (BS1).

Not Met criteria codes

• BA1: 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
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline