rs200605472

Variant names:

• chr17-18167639-G-A
• rs200605472
• NM_016239.4:c.9998G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency (the lower threshold of the 95% CI of 41/10294) of the c.9998G>A (p.Arg3333Gln) variant in the MYO15A gene is 0.302% for Ashkenazi Jewish chromosomes by gnomAD, which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA177281/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00024 (2 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Likely benign reviewed by expert panel B:5
• Conservation: PhyloP100: 0.431

Genes affected

MYO15A (HGNC:7594): (myosin XVA) This gene encodes an unconventional myosin. This protein differs from other myosins in that it has a long N-terminal extension preceding the conserved motor domain. Studies in mice suggest that this protein is necessary for actin organization in the hair cells of the cochlea. Mutations in this gene have been associated with profound, congenital, neurosensory, nonsyndromal deafness. This gene is located within the Smith-Magenis syndrome region on chromosome 17. Read-through transcripts containing an upstream gene and this gene have been identified, but they are not thought to encode a fusion protein. Several alternatively spliced transcript variants have been described, but their full length sequences have not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.9998G>A	p.Arg3333Gln	missense_variant	Exon 62 of 66	ENST00000647165.2	NP_057323.3
MYO15A	XM_017024715.3	c.10001G>A	p.Arg3334Gln	missense_variant	Exon 60 of 64		XP_016880204.1
MYO15A	XM_017024714.3	c.9938G>A	p.Arg3313Gln	missense_variant	Exon 59 of 63		XP_016880203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.9998G>A	p.Arg3333Gln	missense_variant	Exon 62 of 66		NM_016239.4	ENSP00000495481.1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152246 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000274 AC: 66 AN: 240818 Hom.: 0 AF XY: 0.000281 AC XY: 37 AN XY: 131774

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00400

Gnomad EAS exome AF: 0.000391

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000714

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000240 AC: 348 AN: 1451708 Hom.: 2 Cov.: 32 AF XY: 0.000227 AC XY: 164 AN XY: 722616

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00391

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000126

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152246 Hom.: 0 Cov.: 34 AF XY: 0.000215 AC XY: 16 AN XY: 74382

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.000770

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000882 Hom.: 0

Bravo AF: 0.000283

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000476 AC: 4

ExAC AF: 0.000314 AC: 38

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 09, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 30, 2016

p.Arg3333Gln in exon 62 of MYO15A: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, many species, including other primates, have a glutamine (Gln) at this p osition despite high nearby amino acid conservation. This variant has been ident ified in 28/64402 European chromosomes by the Exome Aggregation Consortium (ExAC , http://exac.broadinstitute.org; dbSNP rs200605472). -

MYO15A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 29, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Nonsyndromic genetic hearing loss Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Jul 22, 2021

The filtering allele frequency (the lower threshold of the 95% CI of 41/10294) of the c.9998G>A (p.Arg3333Gln) variant in the MYO15A gene is 0.302% for Ashkenazi Jewish chromosomes by gnomAD, which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.1
DANN	Benign	0.81
DEOGEN2	Benign	0.0096	T;T;T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.71	T;.;T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.0096	T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.26	.;N;N;.;.
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.59	.;N;.;.;.
REVEL	Benign	0.20
Sift	Benign	0.40	.;T;.;.;.
Sift4G	Benign	0.38	T;T;.;T;.
Polyphen		0.0040	.;B;B;.;.
Vest4		0.19
MVP		0.26
ClinPred		0.0018	T
GERP RS		-3.4
Varity_R		0.045
gMVP		0.084

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200605472; hg19: chr17-18070953;