17-18120952-T-G

Position:

chr17-18120952-T-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.2152T>G(p.Trp718Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 1,479,028 control chromosomes in the GnomAD database, including 97,834 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 10430 hom., cov: 33)

Exomes 𝑓: 0.35 ( 87404 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.213

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=3.5260234E-6).

BP6

Variant 17-18120952-T-G is Benign according to our data. Variant chr17-18120952-T-G is described in ClinVar as [Benign]. Clinvar id is 226779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18120952-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.686 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.2152T>G	p.Trp718Gly	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.2152T>G	p.Trp718Gly	missense_variant	2/66		NM_016239.4	P1	Q9UKN7-1
MYO15A	ENST00000583079.1 linkuse as main transcript	n.1785T>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.358

AC:

53875

AN:

150502

Hom.:

10419

Cov.:

show subpopulations

Gnomad AFR

AF:

0.302

Gnomad AMI

AF:

0.418

Gnomad AMR

AF:

0.435

Gnomad ASJ

AF:

0.402

Gnomad EAS

AF:

0.636

Gnomad SAS

AF:

0.706

Gnomad FIN

AF:

0.413

Gnomad MID

AF:

0.341

Gnomad NFE

AF:

0.318

Gnomad OTH

AF:

0.361

GnomAD3 exomes

AF:

0.446

AC:

38542

AN:

86400

Hom.:

9681

AF XY:

0.463

AC XY:

22751

AN XY:

49100

show subpopulations

Gnomad AFR exome

AF:

0.278

Gnomad AMR exome

AF:

0.475

Gnomad ASJ exome

AF:

0.398

Gnomad EAS exome

AF:

0.599

Gnomad SAS exome

AF:

0.695

Gnomad FIN exome

AF:

0.387

Gnomad NFE exome

AF:

0.300

Gnomad OTH exome

AF:

0.387

GnomAD4 exome

AF:

0.346

AC:

459558

AN:

1328418

Hom.:

87404

Cov.:

AF XY:

0.357

AC XY:

234014

AN XY:

655368

show subpopulations

Gnomad4 AFR exome

AF:

0.302

Gnomad4 AMR exome

AF:

0.470

Gnomad4 ASJ exome

AF:

0.407

Gnomad4 EAS exome

AF:

0.658

Gnomad4 SAS exome

AF:

0.697

Gnomad4 FIN exome

AF:

0.383

Gnomad4 NFE exome

AF:

0.306

Gnomad4 OTH exome

AF:

0.375

GnomAD4 genome

AF:

0.358

AC:

53913

AN:

150610

Hom.:

10430

Cov.:

AF XY:

0.370

AC XY:

27258

AN XY:

73620

show subpopulations

Gnomad4 AFR

AF:

0.302

Gnomad4 AMR

AF:

0.436

Gnomad4 ASJ

AF:

0.402

Gnomad4 EAS

AF:

0.637

Gnomad4 SAS

AF:

0.706

Gnomad4 FIN

AF:

0.413

Gnomad4 NFE

AF:

0.318

Gnomad4 OTH

AF:

0.361

Alfa

AF:

0.335

Hom.:

1871

Bravo

AF:

0.351

TwinsUK

AF:

0.304

AC:

1128

ALSPAC

AF:

0.299

AC:

1152

ExAC

AF:

0.276

AC:

9882

Asia WGS

AF:

0.621

AC:

2083

AN:

3358

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Trp718Gly in Exon 02 of MYO15A: This variant is not expected to have clinical si gnificance because it has been identified in 17.8% (619/3482) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs2955367). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 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. -

Autosomal recessive nonsyndromic hearing loss 3

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Benign

0.027

T;T;T

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.42

T;.;T

MetaRNN

Benign

0.0000035

T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.8

.;L;L

MutationTaster

Benign

0.87

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-2.2

.;N;.

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

.;D;.

Sift4G

Uncertain

0.011

D;D;.

Polyphen

0.81

.;P;P

Vest4

0.46

ClinPred

0.070

GERP RS

3.0

Varity_R

0.39

gMVP

0.22

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