17-18119796-C-G

Position:

chr17-18119796-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM3_SupportingPVS1PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.996C>G (p.Tyr332Ter) variant in the MYO15A gene is 0.004% (50/1179998) of European non-Finnish alleles by gnomAD v4.1.1, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). The p.Tyr332Ter variant in MYO15A is predicted to cause a premature stop codon in biologically-relevant-exon 2/66 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). One proband with SNHL with a loss of function pathogenic variant but without parent testing was found in LMM internal data (PM3_Supporting). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting, PVS1, PM3_Supporting. (ClinGen Hearing Loss VCEP specifications version 1; 7/23/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8422996/MONDO:0019497/023

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

MYO15A
NM_016239.4 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:4

Conservation

PhyloP100: -1.52

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 Pathogenic. Variant got 10 ACMG points.

PVS1

PM2

PM3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4 linkuse as main transcript	c.996C>G	p.Tyr332Ter	stop_gained	2/66	ENST00000647165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2 linkuse as main transcript	c.996C>G	p.Tyr332Ter	stop_gained	2/66		NM_016239.4	P1	Q9UKN7-1
MYO15A	ENST00000583079.1 linkuse as main transcript	n.629C>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

248990

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135316

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1460854

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

726740

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000432

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000827

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Nonsyndromic genetic hearing loss

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Jul 23, 2024

The allele frequency of the c.996C>G (p.Tyr332Ter) variant in the MYO15A gene is 0.004% (50/1179998) of European non-Finnish alleles by gnomAD v4.1.1, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). The p.Tyr332Ter variant in MYO15A is predicted to cause a premature stop codon in biologically-relevant-exon 2/66 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). One proband with SNHL with a loss of function pathogenic variant but without parent testing was found in LMM internal data (PM3_Supporting). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting, PVS1, PM3_Supporting. (ClinGen Hearing Loss VCEP specifications version 1; 7/23/2024) -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2023

This sequence change creates a premature translational stop signal (p.Tyr332*) in the MYO15A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO15A are known to be pathogenic (PMID: 17546645). This variant is present in population databases (rs759523751, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MYO15A-related conditions. ClinVar contains an entry for this variant (Variation ID: 505185). For these reasons, this variant has been classified as Pathogenic. -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 30, 2016

The p.Tyr332X variant in MYO15A has not been previously reported in individuals with hearing loss. It has been identified in 1/65810 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Althoug h this variant has been seen in the general population, its frequency is low eno ugh to be consistent with the carrier frequency for recessive hearing loss. Thi s nonsense variant leads to a premature termination codon at position 332 which is predicted to lead to a truncated or absent protein. Loss of function of the M YO15A gene is an established disease mechanism in autosomal recessive nonsyndrom ic hearing loss. In summary, this variant meets our criteria to be classified as pathogenic for nonsyndromic hearing loss in an autosomal recessive manner based on the predicted impact of the variant and extremely low allele frequency in th e general population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

0.99

Eigen

Benign

-0.071

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.17

MutationTaster

Benign

1.0

Vest4

0.52

GERP RS

-1.3

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

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