rs3758449

Positions:

chr10-26157383-G-A

Variant summary

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

The NM_017433.5(MYO3A):c.2867G>A(p.Ser956Asn) variant causes a missense change. The variant allele was found at a frequency of 0.533 in 1,613,650 control chromosomes in the GnomAD database, including 231,940 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 20443 hom., cov: 32)

Exomes 𝑓: 0.54 ( 211497 hom. )

Consequence

MYO3A
NM_017433.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 5.36

Variant links:

Genes affected

MYO3A (HGNC:7601): (myosin IIIA) The protein encoded by this gene belongs to the myosin superfamily. Myosins are actin-dependent motor proteins and are categorized into conventional myosins (class II) and unconventional myosins (classes I and III through XV) based on their variable C-terminal cargo-binding domains. Class III myosins, such as this one, have a kinase domain N-terminal to the conserved N-terminal motor domains and are expressed in photoreceptors. The protein encoded by this gene plays an important role in hearing in humans. Three different recessive, loss of function mutations in the encoded protein have been shown to cause nonsyndromic progressive hearing loss. Expression of this gene is highly restricted, with the strongest expression in retina and cochlea. [provided by RefSeq, Jul 2008]

MYO3A links:

MYO3A (HGNC:):

MYO3A 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=7.164611E-5).

BP6

Variant 10-26157383-G-A is Benign according to our data. Variant chr10-26157383-G-A is described in ClinVar as [Benign]. Clinvar id is 45804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-26157383-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO3A	NM_017433.5 linkuse as main transcript	c.2867G>A	p.Ser956Asn	missense_variant	26/35	ENST00000642920.2	NP_059129.3	Q8NEV4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO3A	ENST00000642920.2 linkuse as main transcript	c.2867G>A	p.Ser956Asn	missense_variant	26/35		NM_017433.5	ENSP00000495965.1		Q8NEV4-1

Frequencies

GnomAD3 genomes

AF:

0.514

AC:

78050

AN:

151834

Hom.:

20442

Cov.:

show subpopulations

Gnomad AFR

AF:

0.465

Gnomad AMI

AF:

0.433

Gnomad AMR

AF:

0.481

Gnomad ASJ

AF:

0.528

Gnomad EAS

AF:

0.332

Gnomad SAS

AF:

0.500

Gnomad FIN

AF:

0.589

Gnomad MID

AF:

0.601

Gnomad NFE

AF:

0.555

Gnomad OTH

AF:

0.508

GnomAD3 exomes

AF:

0.502

AC:

126069

AN:

251282

Hom.:

32583

AF XY:

0.508

AC XY:

69015

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.462

Gnomad AMR exome

AF:

0.399

Gnomad ASJ exome

AF:

0.523

Gnomad EAS exome

AF:

0.322

Gnomad SAS exome

AF:

0.486

Gnomad FIN exome

AF:

0.586

Gnomad NFE exome

AF:

0.553

Gnomad OTH exome

AF:

0.515

GnomAD4 exome

AF:

0.535

AC:

782019

AN:

1461698

Hom.:

211497

Cov.:

AF XY:

0.534

AC XY:

388628

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.467

Gnomad4 AMR exome

AF:

0.409

Gnomad4 ASJ exome

AF:

0.517

Gnomad4 EAS exome

AF:

0.339

Gnomad4 SAS exome

AF:

0.487

Gnomad4 FIN exome

AF:

0.581

Gnomad4 NFE exome

AF:

0.551

Gnomad4 OTH exome

AF:

0.525

GnomAD4 genome

AF:

0.514

AC:

78075

AN:

151952

Hom.:

20443

Cov.:

AF XY:

0.514

AC XY:

38203

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.465

Gnomad4 AMR

AF:

0.480

Gnomad4 ASJ

AF:

0.528

Gnomad4 EAS

AF:

0.332

Gnomad4 SAS

AF:

0.499

Gnomad4 FIN

AF:

0.589

Gnomad4 NFE

AF:

0.555

Gnomad4 OTH

AF:

0.508

Alfa

AF:

0.541

Hom.:

57710

Bravo

AF:

0.499

TwinsUK

AF:

0.543

AC:

2015

ALSPAC

AF:

0.544

AC:

2097

ESP6500AA

AF:

0.466

AC:

2054

ESP6500EA

AF:

0.549

AC:

4723

ExAC

AF:

0.506

AC:

61470

Asia WGS

AF:

0.424

AC:

1474

AN:

3478

EpiCase

AF:

0.555

EpiControl

AF:

0.560

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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	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	Ser956Asn in Exon 26 of MYO3A: This variant is not expected to have clinical sig nificance because it has been identified in 46.5% (1739/3738) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs3758449). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Autosomal recessive nonsyndromic hearing loss 30

Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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. -

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	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.26

DEOGEN2

Benign

0.12

T;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.34

.;T

MetaRNN

Benign

0.000072

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.48

N;N

PrimateAI

Uncertain

0.59

PROVEAN

Benign

2.0

.;N

REVEL

Benign

0.14

Sift

Benign

0.75

.;T

Sift4G

Benign

0.82

.;T

Polyphen

0.0

B;B

Vest4

0.033

MPC

0.058

ClinPred

0.0026

GERP RS

4.2

Varity_R

0.10

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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