chr10-26211960-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000543632.5(MYO3A):c.1894C>G(p.Leu632Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00447 in 1,612,298 control chromosomes in the GnomAD database, including 251 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L632P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.023 ( 143 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 108 hom. )

Consequence

MYO3A
ENST00000543632.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.539

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 30
Inheritance: AR, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal dominant 90
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MYO3A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024323165).

BP6

Variant 10-26211960-C-G is Benign according to our data. Variant chr10-26211960-C-G is described in CliVar as Benign. Clinvar id is 45818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-26211960-C-G is described in CliVar as Benign. Clinvar id is 45818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-26211960-C-G is described in CliVar as Benign. Clinvar id is 45818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-26211960-C-G is described in CliVar as Benign. Clinvar id is 45818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-26211960-C-G is described in CliVar as Benign. Clinvar id is 45818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-26211960-C-G is described in CliVar as Benign. Clinvar id is 45818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.074 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO3A	NM_017433.5 link	c.4848C>G	p.Ser1616Ser	synonymous_variant	Exon 35 of 35	ENST00000642920.2	NP_059129.3	Q8NEV4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO3A	ENST00000642920.2 link	c.4848C>G	p.Ser1616Ser	synonymous_variant	Exon 35 of 35		NM_017433.5	ENSP00000495965.1		Q8NEV4-1

Frequencies

GnomAD3 genomes

AF:

0.0228

AC:

3465

AN:

152186

Hom.:

137

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0755

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0180

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.00615

AC:

1535

AN:

249400

AF XY:

0.00473

show subpopulations

Gnomad AFR exome

AF:

0.0781

Gnomad AMR exome

AF:

0.00633

Gnomad ASJ exome

AF:

0.000399

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000373

Gnomad OTH exome

AF:

0.00329

GnomAD4 exome

AF:

0.00254

AC:

3711

AN:

1459994

Hom.:

108

Cov.:

AF XY:

0.00223

AC XY:

1619

AN XY:

725924

show subpopulations

African (AFR)

AF:

0.0785

AC:

2626

AN:

33440

American (AMR)

AF:

0.00741

AC:

331

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.000536

AC:

AN:

26100

East Asian (EAS)

AF:

0.00

AC:

AN:

39632

South Asian (SAS)

AF:

0.000162

AC:

AN:

86170

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53356

Middle Eastern (MID)

AF:

0.00487

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000318

AC:

353

AN:

1110606

Other (OTH)

AF:

0.00572

AC:

345

AN:

60274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

222

444

666

888

1110

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

258

344

430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0230

AC:

3504

AN:

152304

Hom.:

143

Cov.:

AF XY:

0.0231

AC XY:

1723

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0762

AC:

3167

AN:

41550

American (AMR)

AF:

0.0180

AC:

275

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000426

AC:

AN:

68030

Other (OTH)

AF:

0.0156

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

153

305

458

610

763

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00699

Hom.:

Bravo

AF:

0.0253

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0722

AC:

318

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00691

AC:

839

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000475

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 23, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ser1616Ser in Exon 35 of MYO3A: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 6.8% (256/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs56316209). -

not provided

Benign:3

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Autosomal recessive nonsyndromic hearing loss 30

Benign:2

Sep 20, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

3.0

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.013

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.26

MetaRNN

Benign

0.0024

MetaSVM

Benign

-0.95

PhyloP100

0.54

PROVEAN

Benign

-1.3

REVEL

Benign

0.26

Sift

Pathogenic

0.0

Sift4G

Benign

0.34

Polyphen

0.0010

Vest4

0.088

MVP

0.62

ClinPred

0.11

GERP RS

1.5

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over