rs140140417

Positions:

chr17-18155154-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

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. 15/20 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 0.0016 ( 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

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:

LOC105371567 (HGNC:):

LOC105371567 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 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 id is 164555.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=4, Uncertain_significance=1}. Variant chr17-18155154-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4 linkuse as main transcript	c.8269G>A	p.Val2757Met	missense_variant	46/66	ENST00000647165.2	NP_057323.3
LOC105371567	XR_001752809.1 linkuse as main transcript	n.89+98C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 linkuse as main transcript	c.8269G>A	p.Val2757Met	missense_variant	46/66		NM_016239.4	ENSP00000495481	P1	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

GnomAD3 exomes

AF:

0.00233

AC:

579

AN:

248928

Hom.:

AF XY:

0.00237

AC XY:

320

AN XY:

135192

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 SAS exome

AF:

0.00562

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

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.00241

Gnomad4 ASJ exome

AF:

0.00612

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00528

Gnomad4 FIN exome

AF:

0.000207

Gnomad4 NFE exome

AF:

0.00155

Gnomad4 OTH exome

AF:

0.00298

GnomAD4 genome

AF:

0.00158

AC:

241

AN:

152340

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

115

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.00248

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.00181

Gnomad4 OTH

AF:

0.00569

Alfa

AF:

0.00224

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	MYO15A: BS2 -

Autosomal recessive nonsyndromic hearing loss 3

Uncertain:1Benign: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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 30, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 15, 2016

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 17, 2020

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

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;.;.

MutationTaster

Benign

0.76

N;N;N

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

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