rs375290498

chr17-18143580-G-Achr17-18143580-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1 BS2

The NM_016239.4(MYO15A):c.5925G>A(p.Trp1975Ter) 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2 B:4
• Conservation: PhyloP100: 3.20

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 Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.5925G>A	p.Trp1975Ter	stop_gained	26/66	ENST00000647165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.5925G>A	p.Trp1975Ter	stop_gained	26/66		NM_016239.4	P1

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152172 Hom.: 0 Cov.: 32

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.: 2 AF XY: 0.00276 AC XY: 247 AN XY: 89488

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.: 18 Cov.: 31 AF XY: 0.00125 AC XY: 868 AN XY: 695766

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: 79 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.000671 AC XY: 50 AN XY: 74472

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.: 0

Bravo AF: 0.0000982

ExAC AF: 0.00191 AC: 220

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Uncertain:1 Benign:3

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 04, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MYO15A: BS1 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 2020	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -

Autosomal recessive nonsyndromic hearing loss 3 Pathogenic:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 21, 2023	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jun 23, 2014	The variant (c. 5925G>A;p.W1975*) is a nonsense variant, which is predicted to result in a truncated protein and considered pathogenic. -

Rare genetic deafness Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 30, 2022

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	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	37
Dann	Uncertain	0.99
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.75	D
MutationTaster	Benign	1.0	A
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

Other links and lift over

dbSNP: rs375290498; hg19: chr17-18046894;