rs79230542

Positions:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_016239.4(MYO15A):c.10182G>A(p.Ala3394=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00831 in 1,612,076 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0067 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0085 ( 68 hom. )

Consequence

MYO15A
NM_016239.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.91

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009282678).

BP6

Variant 17-18171737-G-A is Benign according to our data. Variant chr17-18171737-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45742.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=5}. Variant chr17-18171737-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-3.91 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MYO15A	NM_016239.4 linkuse as main transcript	c.10182G>A	p.Ala3394=	synonymous_variant	63/66	ENST00000647165.2
MYO15A	XM_017024715.3 linkuse as main transcript	c.10185G>A	p.Ala3395=	synonymous_variant	61/64
MYO15A	XM_017024714.3 linkuse as main transcript	c.10122G>A	p.Ala3374=	synonymous_variant	60/63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2 linkuse as main transcript	c.10182G>A	p.Ala3394=	synonymous_variant	63/66		NM_016239.4	P1	Q9UKN7-1

Frequencies

GnomAD3 genomes

AF:

0.00672

AC:

1023

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00637

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00511

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00347

Gnomad SAS

AF:

0.00622

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00834

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00704

AC:

1728

AN:

245364

Hom.:

AF XY:

0.00706

AC XY:

944

AN XY:

133730

show subpopulations

Gnomad AFR exome

AF:

0.00772

Gnomad AMR exome

AF:

0.00551

Gnomad ASJ exome

AF:

0.00871

Gnomad EAS exome

AF:

0.00291

Gnomad SAS exome

AF:

0.00657

Gnomad FIN exome

AF:

0.00309

Gnomad NFE exome

AF:

0.00863

Gnomad OTH exome

AF:

0.00952

GnomAD4 exome

AF:

0.00848

AC:

12375

AN:

1459800

Hom.:

Cov.:

AF XY:

0.00824

AC XY:

5986

AN XY:

726294

show subpopulations

Gnomad4 AFR exome

AF:

0.00750

Gnomad4 AMR exome

AF:

0.00550

Gnomad4 ASJ exome

AF:

0.00792

Gnomad4 EAS exome

AF:

0.00615

Gnomad4 SAS exome

AF:

0.00653

Gnomad4 FIN exome

AF:

0.00328

Gnomad4 NFE exome

AF:

0.00913

Gnomad4 OTH exome

AF:

0.00810

GnomAD4 genome

AF:

0.00672

AC:

1024

AN:

152276

Hom.:

Cov.:

AF XY:

0.00653

AC XY:

486

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00638

Gnomad4 AMR

AF:

0.00510

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.00347

Gnomad4 SAS

AF:

0.00622

Gnomad4 FIN

AF:

0.00273

Gnomad4 NFE

AF:

0.00834

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00788

Hom.:

Bravo

AF:

0.00729

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00780

AC:

ESP6500EA

AF:

0.00951

AC:

ExAC

AF:

0.00698

AC:

844

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.00883

EpiControl

AF:

0.00854

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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	MYO15A: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2019	This variant is associated with the following publications: (PMID: 24498627) -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 16, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Ala3394Ala in Exon 63 of MYO15A: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 0.9% (29/3294) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs79230542). -

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. -

MYO15A-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2022

This variant is classified as 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

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Uncertain

0.13

CADD

Benign

0.023

DANN

Uncertain

0.98

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.39

M_CAP

Benign

0.053

MetaRNN

Benign

0.0093

MetaSVM

Uncertain

-0.11

MutationTaster

Benign

1.0

D;D;N

MVP

0.081

ClinPred

0.013

GERP RS

-11

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