rs854777

Positions:

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

Scores

Clinical Significance

Benign reviewed by expert panel B:12

Conservation

PhyloP100: -0.0330

Variant links:

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]

MYO15A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	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 linkuse as main transcript	c.5929T>C	p.Cys1977Arg	missense_variant	26/66		NM_016239.4	ENSP00000495481	P1	Q9UKN7-1

Frequencies

GnomAD3 genomes

AF:

0.781

AC:

118665

AN:

151916

Hom.:

46845

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.738

AC XY:

513806

AN XY:

696050

show subpopulations

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.:

AF XY:

0.777

AC XY:

57713

AN XY:

74324

show subpopulations

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

LINK: link

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

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

LIST_S2

Benign

0.12

T;.;T

MetaRNN

Benign

9.6e-7

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.5

.;N;N

MutationTaster

Benign

0.076

PrimateAI

Benign

0.29

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over