rs199695398

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BS1_Supporting

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency (the lower threshold of the 95% CI of 64/23748) of the c.1582G>A (p.Gly528Ser) variant in the MYO15A gene is 0.217% for African/African-American chromosomes by gnomAD, which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8423128/MONDO:0019497/005

Frequency

Genomes: 𝑓 0.00096 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:5

Conservation

PhyloP100: 0.334

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 Likely_benign. Variant got -2 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4 linkuse as main transcript	c.1582G>A	p.Gly528Ser	missense_variant	2/66	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 linkuse as main transcript	c.1582G>A	p.Gly528Ser	missense_variant	2/66		NM_016239.4	ENSP00000495481	P1	Q9UKN7-1
MYO15A	ENST00000583079.1 linkuse as main transcript	n.1215G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.000966

AC:

147

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00323

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000283

AC:

AN:

243688

Hom.:

AF XY:

0.000217

AC XY:

AN XY:

133478

show subpopulations

Gnomad AFR exome

AF:

0.00299

Gnomad AMR exome

AF:

0.000350

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000559

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000910

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.000103

AC:

151

AN:

1459018

Hom.:

Cov.:

AF XY:

0.0000978

AC XY:

AN XY:

725886

show subpopulations

Gnomad4 AFR exome

AF:

0.00311

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000965

AC:

147

AN:

152336

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00322

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000460

Hom.:

Bravo

AF:

0.000979

ESP6500AA

AF:

0.00279

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000249

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2021

The c.1582G>A (p.G528S) alteration is located in exon 2 (coding exon 1) of the MYO15A gene. This alteration results from a G to A substitution at nucleotide position 1582, causing the glycine (G) at amino acid position 528 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 02, 2017

p.Gly528Ser in exon 2 of MYO15A: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, 3 mammals (naked mole-rat, chinchilla, and brush-tailed rat) have a serine (Ser) at this position despite high nearby amino acid sequence conservation. In addition, other computational tools do not suggest an impact to the protein. It has been identified in 0.3% (65/23654) of African chromosomes by the Genome Agg regation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199695398). -

MYO15A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 02, 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). -

Nonsyndromic genetic hearing loss

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Jul 22, 2021

The filtering allele frequency (the lower threshold of the 95% CI of 64/23748) of the c.1582G>A (p.Gly528Ser) variant in the MYO15A gene is 0.217% for African/African-American chromosomes by gnomAD, which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP4. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.0086

T;T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.44

T;.;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.0038

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.55

.;N;N

MutationTaster

Benign

1.0

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.19

.;N;.

REVEL

Benign

0.017

Sift

Benign

0.62

.;T;.

Sift4G

Benign

0.49

T;T;.

Polyphen

0.0070

.;B;B

Vest4

0.12

MVP

0.15

ClinPred

0.00098

GERP RS

-2.1

Varity_R

0.043

gMVP

0.25

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