rs712270

Positions:

chr17-18153853-A-T

Variant summary

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

The NM_016239.4(MYO15A):c.8045A>T(p.Tyr2682Phe) variant causes a missense change. The variant allele was found at a frequency of 0.384 in 1,613,226 control chromosomes in the GnomAD database, including 124,975 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 9358 hom., cov: 32)

Exomes 𝑓: 0.39 ( 115617 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 6.34

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:

LOC105371567 (HGNC:):

LOC105371567 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=0.0023952425).

BP6

Variant 17-18153853-A-T is Benign according to our data. Variant chr17-18153853-A-T is described in ClinVar as [Benign]. Clinvar id is 226790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18153853-A-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4 linkuse as main transcript	c.8045A>T	p.Tyr2682Phe	missense_variant	43/66	ENST00000647165.2	NP_057323.3
LOC105371567	XR_001752809.1 linkuse as main transcript	n.329T>A		non_coding_transcript_exon_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 linkuse as main transcript	c.8045A>T	p.Tyr2682Phe	missense_variant	43/66		NM_016239.4	ENSP00000495481	P1	Q9UKN7-1

Frequencies

GnomAD3 genomes

AF:

0.336

AC:

51019

AN:

151856

Hom.:

9356

Cov.:

show subpopulations

Gnomad AFR

AF:

0.232

Gnomad AMI

AF:

0.428

Gnomad AMR

AF:

0.300

Gnomad ASJ

AF:

0.398

Gnomad EAS

AF:

0.0822

Gnomad SAS

AF:

0.215

Gnomad FIN

AF:

0.423

Gnomad MID

AF:

0.348

Gnomad NFE

AF:

0.418

Gnomad OTH

AF:

0.326

GnomAD3 exomes

AF:

0.336

AC:

83706

AN:

248882

Hom.:

15506

AF XY:

0.336

AC XY:

45427

AN XY:

135276

show subpopulations

Gnomad AFR exome

AF:

0.223

Gnomad AMR exome

AF:

0.286

Gnomad ASJ exome

AF:

0.410

Gnomad EAS exome

AF:

0.0885

Gnomad SAS exome

AF:

0.217

Gnomad FIN exome

AF:

0.437

Gnomad NFE exome

AF:

0.412

Gnomad OTH exome

AF:

0.367

GnomAD4 exome

AF:

0.389

AC:

568319

AN:

1461252

Hom.:

115617

Cov.:

AF XY:

0.384

AC XY:

278872

AN XY:

726932

show subpopulations

Gnomad4 AFR exome

AF:

0.226

Gnomad4 AMR exome

AF:

0.287

Gnomad4 ASJ exome

AF:

0.402

Gnomad4 EAS exome

AF:

0.0988

Gnomad4 SAS exome

AF:

0.217

Gnomad4 FIN exome

AF:

0.437

Gnomad4 NFE exome

AF:

0.421

Gnomad4 OTH exome

AF:

0.363

GnomAD4 genome

AF:

0.336

AC:

51031

AN:

151974

Hom.:

9358

Cov.:

AF XY:

0.330

AC XY:

24513

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.232

Gnomad4 AMR

AF:

0.299

Gnomad4 ASJ

AF:

0.398

Gnomad4 EAS

AF:

0.0828

Gnomad4 SAS

AF:

0.215

Gnomad4 FIN

AF:

0.423

Gnomad4 NFE

AF:

0.418

Gnomad4 OTH

AF:

0.322

Alfa

AF:

0.396

Hom.:

9511

Bravo

AF:

0.320

TwinsUK

AF:

0.419

AC:

1555

ALSPAC

AF:

0.435

AC:

1675

ESP6500AA

AF:

0.227

AC:

861

ESP6500EA

AF:

0.407

AC:

3348

ExAC

AF:

0.334

AC:

40310

Asia WGS

AF:

0.161

AC:

562

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Tyr2682Phe in Exon 43 of MYO15A: This variant is not expected to have clinical s ignificance because it has been identified in 39.8% (2646/6644) of European Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs712270). -

Autosomal recessive nonsyndromic hearing loss 3

Benign:2

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 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 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Benign

0.019

T;T;T

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.80

T;.;T

MetaRNN

Benign

0.0024

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

.;M;M

MutationTaster

Benign

0.000024

P;P

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.5

.;N;.

REVEL

Uncertain

0.35

Sift

Benign

0.25

.;T;.

Sift4G

Benign

0.11

T;T;.

Polyphen

1.0

.;D;D

Vest4

0.36

ClinPred

0.088

GERP RS

5.1

Varity_R

0.19

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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