rs769260536

chr17-18119933-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_016239.4(MYO15A):c.1137del(p.Tyr380MetfsTer64) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,613,320 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

MYO15A
NM_016239.4 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic reviewed by expert panel P:7

Conservation

PhyloP100: -0.803

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 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-18119933-TC-T is Pathogenic according to our data. Variant chr17-18119933-TC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 500061.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-18119933-TC-T is described in Lovd as [Likely_pathogenic]. Variant chr17-18119933-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4 linkuse as main transcript	c.1137del	p.Tyr380MetfsTer64	frameshift_variant	2/66	ENST00000647165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2 linkuse as main transcript	c.1137del	p.Tyr380MetfsTer64	frameshift_variant	2/66		NM_016239.4	P1	Q9UKN7-1
MYO15A	ENST00000583079.1 linkuse as main transcript	n.770del		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.0000987

AC:

AN:

151976

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000177

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000962

AC:

AN:

249352

Hom.:

AF XY:

0.0000739

AC XY:

AN XY:

135376

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

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:

0.000195

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000142

AC:

207

AN:

1461344

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

726968

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

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:

0.000178

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000987

AC:

AN:

151976

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.0000484

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000177

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000144

Hom.:

Bravo

AF:

0.000113

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 3

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Nov 24, 2017	A heterozygous frameshift deletion variant, NM_016239.3(MYO15A):c.1137delC, has been identified in exon 2 of 66 of the MYO15A gene. This deletion is predicted to create a frameshift starting at amino acid position 380, introducing a stop codon 64 residues downstream, NP_057323.3(MYO15A):p.(Tyr380Metfs*64). This variant is predicted to result in loss of protein function either through truncation (loss of majority of the protein, including all functional domains) or nonsense-mediated decay. The variant is present in the gnomAD database at a frequency of 0.01% (28 heterozygotes) andhas been previously described as a compound heterozygote with a second truncating variant in two patients with hearing loss (Schrauwen, I., et al. (2013), Vona, B. et al. (2014)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 01, 2017	The MYO15A c.1137delC (p.Tyr380MetfsTer64) variant is a frameshift variant that is predicted to result in premature termination of the protein. This variant has been reported in a compound heterozygous state along with a second null variant in three individuals with hearing loss (Schrauwen et al. 2013; Neveling et al. 2013; Vona et al. 2014). The individual identified in the Vona et al. (2014) study also carried the c.7C>G (p.Gln3Glu) missense variant in the MYH9 gene. The p.Tyr380MetfsTer64 variant was absent from nine normal hearing controls, but is reported at a frequency of 0.00038 in the European American population of the Exome Sequencing Project. Based on the evidence and due to the potential impact of frameshift variants, the p.Tyr380MetfsTer64 is classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change creates a premature translational stop signal (p.Tyr380Metfs*64) 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 (rs769260536, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with MYO15A-related conditions (PMID: 23208854, 24123792). This variant is also known as c.1134delC. ClinVar contains an entry for this variant (Variation ID: 500061). For these reasons, this variant has been classified as Pathogenic. -

Nonsyndromic genetic hearing loss

Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Mar 20, 2024

The c.1137del (p.Tyr380fsTer64) variant in MYO15A is frameshift variant in biologically relevant exon 2/66 that is predicted to lead to a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4.0.0 is 210/1179974 alleles (0.0001780 or 0.0178 %) in the European (non-Finnish) population (PM2_supporting, BS1, and BA1 not met). This variant has been detected in 3 individuals with nonsyndromic hearing loss. For each of those individuals, they were compound heterozygous for the variant and a pathogenic or likely pathogenic variant, but phase was not confirmed (p.Lys1003fsTer55, p.Glu209Ter, p.Arg3134Ter; PMIDs: 23208854, 28000701, 31980526; 1.5 pts. PM3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: (PVS1, PM3; Version 1; 3/20/2024). -

Hearing impairment

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PVS1_Very strong, PS1_Strong, PM2_Supporting, PP1_Supporting -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 02, 2020

The p.Tyr380MetfsX64 variant in MYO15A has been previously reported in at least 3 individuals with hearing loss who were compound heterozygous for a second truncating MYO15A variant (Neveling 2013, Schrauwen 2013, Vona 2014, Zazo Seco 2017, Hou 2020). This variant has been identified in 0.02% (26/128476) of European chromosomes by gnomad chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the proteinâ€™s amino acid sequence beginning at position 380 and leads to a premature termination codon 64 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MYO15A gene is an established disease mechanism in autosomal recessive hearing loss. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_Strong. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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