rs375290498

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 8P and 5B. PVS1BS1_SupportingBS2

The NM_016239.4(MYO15A):c.5925G>A(p.Trp1975*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00086 in 1,560,974 control chromosomes in the GnomAD database, including 18 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00090 ( 18 hom. )

Consequence

MYO15A
NM_016239.4 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:3B:4

Conservation

PhyloP100: 3.20

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 Uncertain_significance. Variant got 3 ACMG points.

PVS1

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

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000519 (79/152290) while in subpopulation SAS AF= 0.0152 (73/4818). AF 95% confidence interval is 0.0124. There are 0 homozygotes in gnomad4. There are 50 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4 link	c.5925G>A	p.Trp1975*	stop_gained	Exon 26 of 66	ENST00000647165.2	NP_057323.3	Q9UKN7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 link	c.5925G>A	p.Trp1975*	stop_gained	Exon 26 of 66		NM_016239.4	ENSP00000495481.1		Q9UKN7-1

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0151

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00197

AC:

330

AN:

167876

Hom.:

AF XY:

0.00276

AC XY:

247

AN XY:

89488

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000154

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0132

Gnomad FIN exome

AF:

0.0000633

Gnomad NFE exome

AF:

0.000133

Gnomad OTH exome

AF:

0.00109

GnomAD4 exome

AF:

0.000897

AC:

1263

AN:

1408684

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

868

AN XY:

695766

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000108

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000272

Gnomad4 SAS exome

AF:

0.0139

Gnomad4 FIN exome

AF:

0.0000200

Gnomad4 NFE exome

AF:

0.0000655

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.000519

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000671

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0152

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000889

Hom.:

Bravo

AF:

0.0000982

ExAC

AF:

0.00191

AC:

220

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:1Benign:3

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 23, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29907799, 22736430, 10552926, 27375115, 26969326, 30096381, 31130284) -

Mar 04, 2021

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYO15A: BS1 -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 3

Pathogenic:1Uncertain:1Benign:1

Aug 09, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 23, 2014

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The variant (c. 5925G>A;p.W1975*) is a nonsense variant, which is predicted to result in a truncated protein and considered pathogenic. -

Nov 21, 2023

Revvity Omics, Revvity

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rare genetic deafness

Uncertain:1

Jun 30, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Trp1975X variant in MYO15A has been reported in one Iranian individual with nonsyndromic hearing loss and segregated with disease in 6 family members, all of whom were homozygous for the variant (Fattahi 2012). However, this variant has also been identified in 1.7% (138/8086) of South Asian chromosomes including 2 individuals who were homozygous by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs375290498). In addition, this nonsense variant introduces a premature codon at position 1975 in exon 26 of the MYO15A; exon 26 is missing in some alternatively spliced transcripts of MYO15A identified in the inner ear (Liang 1999), raising the possibility that this exon may not be functionally relevant. Although the segregation data reported in the Iranian family above (Fattahi 2012) suggests pathogenicity for this variant, it is not uncommon to detect homozygous variants in families with consanguinity and/or in isolated ethnic groups as is the case with this family, and it is possible that another variant on the same chromosome as this variant is causative for disease in the family. In summary, due to conflicting data, the clinical significance of the p.Trp1975X variant is uncertain.. ACMG/AMP Criteria applied: BA1. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Benign

0.75

Vest4

0.36

GERP RS

3.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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