17-18122213-A-G

Position:

chr17-18122213-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016239.4(MYO15A):c.3413A>G(p.Gln1138Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00654 in 1,613,148 control chromosomes in the GnomAD database, including 300 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 71 hom., cov: 33)

Exomes 𝑓: 0.0052 ( 229 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.510

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=0.0018774569).

BP6

Variant 17-18122213-A-G is Benign according to our data. Variant chr17-18122213-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 226784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18122213-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0995 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4 linkuse as main transcript	c.3413A>G	p.Gln1138Arg	missense_variant	2/66	ENST00000647165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2 linkuse as main transcript	c.3413A>G	p.Gln1138Arg	missense_variant	2/66		NM_016239.4	P1	Q9UKN7-1
MYO15A	ENST00000583079.1 linkuse as main transcript	n.3046A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.0191

AC:

2910

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00674

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.107

Gnomad SAS

AF:

0.00868

Gnomad FIN

AF:

0.00837

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00100

Gnomad OTH

AF:

0.0143

GnomAD3 exomes

AF:

0.0139

AC:

3447

AN:

248824

Hom.:

132

AF XY:

0.0125

AC XY:

1689

AN XY:

135266

show subpopulations

Gnomad AFR exome

AF:

0.0481

Gnomad AMR exome

AF:

0.00333

Gnomad ASJ exome

AF:

0.00249

Gnomad EAS exome

AF:

0.113

Gnomad SAS exome

AF:

0.00549

Gnomad FIN exome

AF:

0.00779

Gnomad NFE exome

AF:

0.00136

Gnomad OTH exome

AF:

0.00778

GnomAD4 exome

AF:

0.00523

AC:

7633

AN:

1460848

Hom.:

229

Cov.:

AF XY:

0.00508

AC XY:

3690

AN XY:

726714

show subpopulations

Gnomad4 AFR exome

AF:

0.0498

Gnomad4 AMR exome

AF:

0.00367

Gnomad4 ASJ exome

AF:

0.00233

Gnomad4 EAS exome

AF:

0.0858

Gnomad4 SAS exome

AF:

0.00546

Gnomad4 FIN exome

AF:

0.00811

Gnomad4 NFE exome

AF:

0.000665

Gnomad4 OTH exome

AF:

0.0109

GnomAD4 genome

AF:

0.0191

AC:

2910

AN:

152300

Hom.:

Cov.:

AF XY:

0.0192

AC XY:

1433

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0484

Gnomad4 AMR

AF:

0.00673

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.107

Gnomad4 SAS

AF:

0.00869

Gnomad4 FIN

AF:

0.00837

Gnomad4 NFE

AF:

0.00100

Gnomad4 OTH

AF:

0.0151

Alfa

AF:

0.00760

Hom.:

Bravo

AF:

0.0214

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0425

AC:

173

ESP6500EA

AF:

0.000958

AC:

ExAC

AF:

0.0141

AC:

1703

Asia WGS

AF:

0.0410

AC:

144

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.000948

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 17, 2015	p.Gln1138Arg in exon 2 of MYO15A: This variant is not expected to have clinical significance because it has been identified in 10.9% (939/8600) of East Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs76468019). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive nonsyndromic hearing loss 3

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.50

CADD

Benign

0.18

DANN

Benign

0.19

DEOGEN2

Benign

0.0094

T;T;T

Eigen

Benign

-2.6

Eigen_PC

Benign

-2.5

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.17

T;.;T

MetaRNN

Benign

0.0019

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

.;L;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.020

.;N;.

REVEL

Benign

0.16

Sift

Benign

0.51

.;T;.

Sift4G

Benign

0.89

T;T;.

Polyphen

0.0

.;B;B

Vest4

0.014

ClinPred

0.0097

GERP RS

-3.5

Varity_R

0.029

gMVP

0.12

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