rs140140417

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_016239.4(MYO15A):c.8269G>A(p.Val2757Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,613,966 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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 0.0016 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 9 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 1.13

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MYO15A links:

LOC105371567 (HGNC:):

LOC105371567 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0064539015).

BP6

Variant 17-18155154-G-A is Benign according to our data. Variant chr17-18155154-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 164555.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00158 (241/152340) while in subpopulation SAS AF = 0.00435 (21/4830). AF 95% confidence interval is 0.00291. There are 1 homozygotes in GnomAd4. There are 115 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4 link	c.8269G>A	p.Val2757Met	missense_variant	Exon 46 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.8269G>A	p.Val2757Met	missense_variant	Exon 46 of 66		NM_016239.4	ENSP00000495481.1		Q9UKN7-1

Frequencies

GnomAD3 genomes

AF:

0.00157

AC:

239

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00181

Gnomad OTH

AF:

0.00575

GnomAD2 exomes

AF:

0.00233

AC:

579

AN:

248928

AF XY:

0.00237

show subpopulations

Gnomad AFR exome

AF:

0.000454

Gnomad AMR exome

AF:

0.00275

Gnomad ASJ exome

AF:

0.00468

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00212

Gnomad OTH exome

AF:

0.00231

GnomAD4 exome

AF:

0.00188

AC:

2747

AN:

1461626

Hom.:

Cov.:

AF XY:

0.00205

AC XY:

1491

AN XY:

727106

show subpopulations

African (AFR)

AF:

0.000538

AC:

AN:

33478

American (AMR)

AF:

0.00241

AC:

108

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00612

AC:

160

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00528

AC:

455

AN:

86256

European-Finnish (FIN)

AF:

0.000207

AC:

AN:

53186

Middle Eastern (MID)

AF:

0.0147

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00155

AC:

1729

AN:

1111996

Other (OTH)

AF:

0.00298

AC:

180

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

199

397

596

794

993

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00158

AC:

241

AN:

152340

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

115

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000409

AC:

AN:

41570

American (AMR)

AF:

0.00248

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.000578

AC:

AN:

5190

South Asian (SAS)

AF:

0.00435

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00181

AC:

123

AN:

68026

Other (OTH)

AF:

0.00569

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00203

Hom.:

Bravo

AF:

0.00189

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00213

AC:

ExAC

AF:

0.00226

AC:

274

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00278

EpiControl

AF:

0.00284

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYO15A: BS2 -

Apr 08, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 3

Uncertain:1Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jul 30, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jan 15, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Val2757Met in exon 46 of MYO15A: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, hedgehog, elephant, hyrax and platypus have a methionine (Met) at this position despite high nearby amino acid conservation. In addition, this variant has been identified in 0.6% (94/16282) of South Asian chromosomes including 1 ho mozygote by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs140140417). -

MYO15A-related disorder

Benign:1

Mar 17, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

0.088

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.047

T;T;T;.;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.72

T;.;T;T;T

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.0065

T;T;T;T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

1.5

.;L;L;.;.

PhyloP100

1.1

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.2

.;N;.;.;.

REVEL

Benign

0.28

Sift

Benign

0.048

.;D;.;.;.

Sift4G

Benign

0.13

T;T;.;D;.

Polyphen

0.15

.;B;B;.;.

Vest4

0.28

MVP

0.60

ClinPred

0.0048

GERP RS

-0.24

Varity_R

0.077

gMVP

0.45

Mutation Taster

=87/13

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over