chr17-18143584-T-C

Position:

• chr17-18143584-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency (the lower threshold of the 95% CI of 15730/17934) of the p.Cys1977Arg variant in the MYO15A gene is 86.6% for African chromosomes (including 6913 homozygous observations) by gnomAD v2.1, 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). ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA136998/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.78 (46916 hom., cov: 31)
  • Exomes 𝑓: 0.74 (391627 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Benign reviewed by expert panel B:12
• Conservation: PhyloP100: -0.0330

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 Benign. Variant got -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.5929T>C	p.Cys1977Arg	missense_variant	26/66	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.5929T>C	p.Cys1977Arg	missense_variant	26/66		NM_016239.4	ENSP00000495481	P1

Frequencies

GnomAD3 genomes AF: 0.781 AC: 118665 AN: 151916 Hom.: 46845 Cov.: 31

Gnomad AFR AF: 0.878

Gnomad AMI AF: 0.656

Gnomad AMR AF: 0.777

Gnomad ASJ AF: 0.807

Gnomad EAS AF: 0.627

Gnomad SAS AF: 0.578

Gnomad FIN AF: 0.755

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.754

Gnomad OTH AF: 0.778

GnomAD3 exomes AF: 0.732 AC: 123555 AN: 168796 Hom.: 45928 AF XY: 0.721 AC XY: 64897 AN XY: 90026

Gnomad AFR exome AF: 0.877

Gnomad AMR exome AF: 0.778

Gnomad ASJ exome AF: 0.817

Gnomad EAS exome AF: 0.624

Gnomad SAS exome AF: 0.580

Gnomad FIN exome AF: 0.758

Gnomad NFE exome AF: 0.749

Gnomad OTH exome AF: 0.752

GnomAD4 exome AF: 0.743 AC: 1047626 AN: 1409088 Hom.: 391627 Cov.: 78 AF XY: 0.738 AC XY: 513806 AN XY: 696050

Gnomad4 AFR exome AF: 0.884

Gnomad4 AMR exome AF: 0.778

Gnomad4 ASJ exome AF: 0.815

Gnomad4 EAS exome AF: 0.620

Gnomad4 SAS exome AF: 0.588

Gnomad4 FIN exome AF: 0.761

Gnomad4 NFE exome AF: 0.751

Gnomad4 OTH exome AF: 0.751

GnomAD4 genome AF: 0.781 AC: 118797 AN: 152034 Hom.: 46916 Cov.: 31 AF XY: 0.777 AC XY: 57713 AN XY: 74324

Gnomad4 AFR AF: 0.878

Gnomad4 AMR AF: 0.778

Gnomad4 ASJ AF: 0.807

Gnomad4 EAS AF: 0.627

Gnomad4 SAS AF: 0.578

Gnomad4 FIN AF: 0.755

Gnomad4 NFE AF: 0.754

Gnomad4 OTH AF: 0.780

Alfa AF: 0.764 Hom.: 46663

Bravo AF: 0.788

TwinsUK AF: 0.748 AC: 2773

ALSPAC AF: 0.746 AC: 2875

ESP6500AA AF: 0.871 AC: 3531

ESP6500EA AF: 0.770 AC: 6375

ExAC AF: 0.684 AC: 73724

Asia WGS AF: 0.608 AC: 2116 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Cys1977Arg in Exon 26 of MYO15A: This variant is not expected to have clinical s ignificance because it has been identified in 23.0% (1535/6674) of European Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs854777). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 26, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Autosomal recessive nonsyndromic hearing loss 3 Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Nonsyndromic genetic hearing loss Benign:1

Benign, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Jun 16, 2021

The filtering allele frequency (the lower threshold of the 95% CI of 15730/17934) of the p.Cys1977Arg variant in the MYO15A gene is 86.6% for African chromosomes (including 6913 homozygous observations) by gnomAD v2.1, 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). ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BA1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	3.6
DANN	Benign	0.45
DEOGEN2	Benign	0.0029	T;T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.12	T;.;T
MetaRNN	Benign	9.6e-7	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.5	.;N;N
MutationTaster	Benign	0.076	P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	3.0	.;N;.
REVEL	Benign	0.26
Sift	Benign	1.0	.;T;.
Sift4G	Benign	0.88	T;T;.
Polyphen		0.0	.;B;B
Vest4		0.029
ClinPred		0.0012	T
GERP RS		1.2
Varity_R		0.066
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs854777; hg19: chr17-18046898; COSMIC: COSV52752023; COSMIC: COSV52752023;