chr17-18120583-G-A

Position:

chr17-18120583-G-A

Variant summary

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

The NM_016239.4(MYO15A):c.1783G>A(p.Ala595Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 1,595,982 control chromosomes in the GnomAD database, including 117,170 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 13693 hom., cov: 33)

Exomes 𝑓: 0.36 ( 103477 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.806

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=3.0458145E-6).

BP6

Variant 17-18120583-G-A is Benign according to our data. Variant chr17-18120583-G-A is described in ClinVar as [Benign]. Clinvar id is 195315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18120583-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.685 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.1783G>A	p.Ala595Thr	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.1783G>A	p.Ala595Thr	missense_variant	2/66		NM_016239.4	P1	Q9UKN7-1
MYO15A	ENST00000583079.1 linkuse as main transcript	n.1416G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.411

AC:

62429

AN:

151736

Hom.:

13661

Cov.:

show subpopulations

Gnomad AFR

AF:

0.479

Gnomad AMI

AF:

0.417

Gnomad AMR

AF:

0.463

Gnomad ASJ

AF:

0.416

Gnomad EAS

AF:

0.635

Gnomad SAS

AF:

0.704

Gnomad FIN

AF:

0.415

Gnomad MID

AF:

0.404

Gnomad NFE

AF:

0.321

Gnomad OTH

AF:

0.399

GnomAD3 exomes

AF:

0.453

AC:

96609

AN:

213070

Hom.:

23637

AF XY:

0.461

AC XY:

54420

AN XY:

118148

show subpopulations

Gnomad AFR exome

AF:

0.499

Gnomad AMR exome

AF:

0.506

Gnomad ASJ exome

AF:

0.423

Gnomad EAS exome

AF:

0.634

Gnomad SAS exome

AF:

0.710

Gnomad FIN exome

AF:

0.403

Gnomad NFE exome

AF:

0.331

Gnomad OTH exome

AF:

0.429

GnomAD4 exome

AF:

0.361

AC:

521016

AN:

1444136

Hom.:

103477

Cov.:

AF XY:

0.371

AC XY:

266445

AN XY:

717532

show subpopulations

Gnomad4 AFR exome

AF:

0.496

Gnomad4 AMR exome

AF:

0.501

Gnomad4 ASJ exome

AF:

0.422

Gnomad4 EAS exome

AF:

0.655

Gnomad4 SAS exome

AF:

0.702

Gnomad4 FIN exome

AF:

0.387

Gnomad4 NFE exome

AF:

0.310

Gnomad4 OTH exome

AF:

0.395

GnomAD4 genome

AF:

0.412

AC:

62511

AN:

151846

Hom.:

13693

Cov.:

AF XY:

0.422

AC XY:

31300

AN XY:

74216

show subpopulations

Gnomad4 AFR

AF:

0.479

Gnomad4 AMR

AF:

0.464

Gnomad4 ASJ

AF:

0.416

Gnomad4 EAS

AF:

0.636

Gnomad4 SAS

AF:

0.704

Gnomad4 FIN

AF:

0.415

Gnomad4 NFE

AF:

0.321

Gnomad4 OTH

AF:

0.399

Alfa

AF:

0.335

Hom.:

7955

Bravo

AF:

0.414

TwinsUK

AF:

0.304

AC:

1129

ALSPAC

AF:

0.300

AC:

1157

ESP6500AA

AF:

0.428

AC:

1422

ESP6500EA

AF:

0.294

AC:

2198

ExAC

AF:

0.427

AC:

49100

Asia WGS

AF:

0.651

AC:

2250

AN:

3460

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 16, 2015	p.Ala595Thr in exon 2 of MYO15A: This variant is not expected to have clinical s ignificance because it has been identified in 52.9% (41979/79374) of chromosomes across various populations by the Exome Aggregation Consortium (ExAC, http://ex ac.broadinstitute.org; dbSNP rs2955365). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	-	- -

Autosomal recessive nonsyndromic hearing loss 3

Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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: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

0.11

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.016

T;T;T

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.066

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.57

T;.;T

MetaRNN

Benign

0.0000030

T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.4

.;L;L

MutationTaster

Benign

0.88

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.68

.;N;.

REVEL

Uncertain

0.32

Sift

Uncertain

0.0030

.;D;.

Sift4G

Uncertain

0.011

D;D;.

Polyphen

0.69

.;P;P

Vest4

0.24

ClinPred

0.050

GERP RS

3.6

Varity_R

0.097

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