rs145292219

Positions:

chr17-18120185-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_016239.4(MYO15A):c.1385G>A(p.Gly462Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00361 in 1,612,888 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0033 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0036 ( 20 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.95

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044930875).

BP6

Variant 17-18120185-G-A is Benign according to our data. Variant chr17-18120185-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18120185-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00326 (496/152350) while in subpopulation AMR AF= 0.00608 (93/15306). AF 95% confidence interval is 0.00508. There are 2 homozygotes in gnomad4. There are 260 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4 link	c.1385G>A	p.Gly462Asp	missense_variant	2/66	ENST00000647165.2	NP_057323.3	Q9UKN7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 link	c.1385G>A	p.Gly462Asp	missense_variant	2/66		NM_016239.4	ENSP00000495481.1		Q9UKN7-1
MYO15A	ENST00000583079.1 link	n.1018G>A		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes

AF:

0.00326

AC:

497

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00608

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.00461

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00444

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00359

AC:

890

AN:

248076

Hom.:

AF XY:

0.00363

AC XY:

490

AN XY:

134990

show subpopulations

Gnomad AFR exome

AF:

0.000975

Gnomad AMR exome

AF:

0.00418

Gnomad ASJ exome

AF:

0.00130

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.00183

Gnomad FIN exome

AF:

0.00265

Gnomad NFE exome

AF:

0.00502

Gnomad OTH exome

AF:

0.00662

GnomAD4 exome

AF:

0.00364

AC:

5320

AN:

1460538

Hom.:

Cov.:

AF XY:

0.00368

AC XY:

2673

AN XY:

726562

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

Gnomad4 AMR exome

AF:

0.00434

Gnomad4 ASJ exome

AF:

0.00138

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00179

Gnomad4 FIN exome

AF:

0.00215

Gnomad4 NFE exome

AF:

0.00405

Gnomad4 OTH exome

AF:

0.00349

GnomAD4 genome

AF:

0.00326

AC:

496

AN:

152350

Hom.:

Cov.:

AF XY:

0.00349

AC XY:

260

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000649

Gnomad4 AMR

AF:

0.00608

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00461

Gnomad4 NFE

AF:

0.00444

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00479

Hom.:

Bravo

AF:

0.00310

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000235

AC:

ESP6500EA

AF:

0.00474

AC:

ExAC

AF:

0.00350

AC:

424

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00622

EpiControl

AF:

0.00658

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2019	This variant is associated with the following publications: (PMID: 24498627) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	MYO15A: BS2 -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Gly462Asp in Exon 02 of MYO15A: This variant is not expected to have clinical si gnificance because it has been identified in 0.5% (32/6856) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs145292219). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 25, 2016	- -

MYO15A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 19, 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). -

Autosomal recessive nonsyndromic hearing loss 3

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.031

T;T;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.033

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.71

T;.;T

M_CAP

Benign

0.0085

MetaRNN

Benign

0.0045

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

.;L;L

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-2.1

.;N;.

REVEL

Benign

0.14

Sift

Benign

0.086

.;T;.

Sift4G

Benign

0.25

T;T;.

Polyphen

0.11

.;B;B

Vest4

0.45

MVP

0.47

ClinPred

0.0088

GERP RS

4.4

Varity_R

0.14

gMVP

0.54

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