rs201794569

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_016239.4(MYO15A):c.1387A>G(p.Met463Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,612,908 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 3 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.94

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.011315584).

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4 linkuse as main transcript	c.1387A>G	p.Met463Val	missense_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.1387A>G	p.Met463Val	missense_variant	2/66		NM_016239.4	P1	Q9UKN7-1
MYO15A	ENST00000583079.1 linkuse as main transcript	n.1020A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.00104

AC:

159

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00289

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00173

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00127

AC:

315

AN:

248164

Hom.:

AF XY:

0.00144

AC XY:

195

AN XY:

135016

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.000638

Gnomad ASJ exome

AF:

0.00290

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.00245

Gnomad FIN exome

AF:

0.0000929

Gnomad NFE exome

AF:

0.00154

Gnomad OTH exome

AF:

0.00182

GnomAD4 exome

AF:

0.00142

AC:

2076

AN:

1460570

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

1086

AN XY:

726582

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.00268

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00225

Gnomad4 FIN exome

AF:

0.000153

Gnomad4 NFE exome

AF:

0.00152

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.00105

AC:

160

AN:

152338

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00173

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00138

Hom.:

Bravo

AF:

0.000963

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000234

AC:

ESP6500EA

AF:

0.00154

AC:

ExAC

AF:

0.00125

AC:

151

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00164

EpiControl

AF:

0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2021	This variant is associated with the following publications: (PMID: 27375115, 30953472, 25262649, 22736430, 22903915, 30245029) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	MYO15A: BP4, BS2 -

Autosomal recessive nonsyndromic hearing loss 3

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 25, 2017

p.Met463Val in exon 2 of MYO15A: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (29/10144) Ashkenazi Jewish c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org; dbSNP rs201794569). In addition, although this variant was previously reported in a family with hearing loss, it was in cis with a pathogenic loss of function variant that was the likely explanation of the hearing loss in that fam ily (Fattahi 2012). -

MYO15A-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 18, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.015

T;T;T

Eigen

Benign

-0.15

Eigen_PC

Benign

0.057

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.65

T;.;T

M_CAP

Benign

0.0061

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

.;L;L

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.3

.;N;.

REVEL

Benign

0.086

Sift

Benign

0.096

.;T;.

Sift4G

Benign

0.091

T;T;.

Polyphen

0.070

.;B;B

Vest4

0.37

MVP

0.33

ClinPred

0.0075

GERP RS

5.4

Varity_R

0.17

gMVP

0.64

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