Variant: NM_016239.4(MYO15A):c.2238G>T (p.Arg746Ser)

CA8423237

226780 (ClinVar)

Gene: MYO15A

Condition: nonsyndromic genetic deafness

Inheritance Mode: Autosomal recessive inheritance

UUID: c106e1bb-b977-487c-8f1d-a99424ff232a

HGVS expressions

NM_016239.4:c.2238G>T
NM_016239.4(MYO15A):c.2238G>T (p.Arg746Ser)
NC_000017.11:g.18121038G>T
CM000679.2:g.18121038G>T
NC_000017.10:g.18024352G>T
CM000679.1:g.18024352G>T
NC_000017.9:g.17965077G>T
NG_011634.1:g.17333G>T
NG_011634.2:g.17333G>T
ENST00000647165.2:c.2238G>T
ENST00000205890.9:c.2238G>T
ENST00000583079.1:n.1871G>T
ENST00000615845.4:c.2238G>T
NM_016239.3:c.2238G>T

Benign

• Met criteria codes: BA1 BP4

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The filtering allele frequency (the lower threshold of the 95% CI of 511/11092) of the p.Arg746Ser variant in the MYO15A gene is 4.27% for African chromosomes (including 8 homozygous observations) by gnomAD, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BA1, BP4.

Met criteria codes

• BA1: The p.Arg746Ser variant is present in 511/11092 African alleles (with 8 homozygous observations) in gnomAD v2.1.1. The lower bound of the 95% CI for MAF is 0.0427 (4.27%). BA1 is met. There is a warning for low coverage. However, the genome-level coverage is good for this site and with genomes only included, the AF in the African population is still at approx 4%.
• BP4: The REVEL score is 0.118, which is below the benign cutoff of 0.15. MaxEnt scan does not predict any impact to splicing. The site is also relatively well conserved in mammals.

Approved on: 2021-06-15

Published on: 2022-05-13