rs3824700

Positions:

chr10-26066977-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.956G>A(p.Arg319His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.522 in 1,599,846 control chromosomes in the GnomAD database, including 223,766 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 17966 hom., cov: 33)

Exomes 𝑓: 0.53 ( 205800 hom. )

Consequence

MYO3A
NM_017433.5 missense, splice_region

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.70

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=5.898216E-5).

BP6

Variant 10-26066977-G-A is Benign according to our data. Variant chr10-26066977-G-A is described in ClinVar as [Benign]. Clinvar id is 45823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-26066977-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.551 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.956G>A	p.Arg319His	missense_variant, splice_region_variant	11/35	ENST00000642920.2	NP_059129.3	Q8NEV4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYO3A	ENST00000642920.2 linkuse as main transcript	c.956G>A	p.Arg319His	missense_variant, splice_region_variant	11/35		NM_017433.5	ENSP00000495965.1	Q8NEV4-1
MYO3A	ENST00000543632.5 linkuse as main transcript	c.956G>A	p.Arg319His	missense_variant, splice_region_variant	10/17	1		ENSP00000445909.1	F5H0U9
MYO3A	ENST00000642197.1 linkuse as main transcript	n.1160G>A		splice_region_variant, non_coding_transcript_exon_variant	11/27
MYO3A	ENST00000647478.1 linkuse as main transcript	n.956G>A		splice_region_variant, non_coding_transcript_exon_variant	10/30			ENSP00000493932.1	A0A2R8Y4D5

Frequencies

GnomAD3 genomes

AF:

0.475

AC:

72235

AN:

151918

Hom.:

17961

Cov.:

show subpopulations

Gnomad AFR

AF:

0.360

Gnomad AMI

AF:

0.432

Gnomad AMR

AF:

0.410

Gnomad ASJ

AF:

0.534

Gnomad EAS

AF:

0.271

Gnomad SAS

AF:

0.495

Gnomad FIN

AF:

0.580

Gnomad MID

AF:

0.608

Gnomad NFE

AF:

0.555

Gnomad OTH

AF:

0.478

GnomAD3 exomes

AF:

0.479

AC:

120193

AN:

251002

Hom.:

30489

AF XY:

0.490

AC XY:

66484

AN XY:

135668

show subpopulations

Gnomad AFR exome

AF:

0.353

Gnomad AMR exome

AF:

0.319

Gnomad ASJ exome

AF:

0.528

Gnomad EAS exome

AF:

0.272

Gnomad SAS exome

AF:

0.482

Gnomad FIN exome

AF:

0.579

Gnomad NFE exome

AF:

0.554

Gnomad OTH exome

AF:

0.504

GnomAD4 exome

AF:

0.527

AC:

763105

AN:

1447810

Hom.:

205800

Cov.:

AF XY:

0.527

AC XY:

380281

AN XY:

721052

show subpopulations

Gnomad4 AFR exome

AF:

0.357

Gnomad4 AMR exome

AF:

0.330

Gnomad4 ASJ exome

AF:

0.521

Gnomad4 EAS exome

AF:

0.263

Gnomad4 SAS exome

AF:

0.482

Gnomad4 FIN exome

AF:

0.575

Gnomad4 NFE exome

AF:

0.552

Gnomad4 OTH exome

AF:

0.515

GnomAD4 genome

AF:

0.475

AC:

72253

AN:

152036

Hom.:

17966

Cov.:

AF XY:

0.475

AC XY:

35278

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.360

Gnomad4 AMR

AF:

0.409

Gnomad4 ASJ

AF:

0.534

Gnomad4 EAS

AF:

0.272

Gnomad4 SAS

AF:

0.494

Gnomad4 FIN

AF:

0.580

Gnomad4 NFE

AF:

0.555

Gnomad4 OTH

AF:

0.479

Alfa

AF:

0.530

Hom.:

41742

Bravo

AF:

0.451

TwinsUK

AF:

0.545

AC:

2020

ALSPAC

AF:

0.542

AC:

2090

ESP6500AA

AF:

0.368

AC:

1621

ESP6500EA

AF:

0.550

AC:

4731

ExAC

AF:

0.485

AC:

58845

Asia WGS

AF:

0.397

AC:

1382

AN:

3478

EpiCase

AF:

0.556

EpiControl

AF:

0.561

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Arg319His in Exon 11 of MYO3A: This variant is not expected to have clinical sig nificance because it has been identified in 45.0% (3157/7020) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs3824700). -

Autosomal recessive nonsyndromic hearing loss 30

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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.15

DEOGEN2

Benign

0.035

T;T;T

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.14

.;T;T

MetaRNN

Benign

0.000059

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-2.6

N;N;.

PrimateAI

Benign

0.41

PROVEAN

Benign

4.2

.;N;N

REVEL

Uncertain

0.30

Sift

Benign

1.0

.;T;T

Sift4G

Benign

1.0

.;T;T

Polyphen

0.0

B;B;B

Vest4

0.082, 0.043

MPC

0.074

ClinPred

0.014

GERP RS

5.6

Varity_R

0.051

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