10-26067063-A-G

Variant names:

Variant summary

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

The NM_017433.5(MYO3A):c.1042A>G(p.Ile348Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.686 in 1,603,116 control chromosomes in the GnomAD database, including 378,441 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. I348L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.69 ( 35977 hom., cov: 32)

Exomes 𝑓: 0.69 ( 342464 hom. )

Consequence

MYO3A
NM_017433.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.06

Publications

38 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=1.3441309E-6).

BP6

Variant 10-26067063-A-G is Benign according to our data. Variant chr10-26067063-A-G is described in ClinVar as Benign. ClinVar VariationId is 45792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO3A	NM_017433.5 link	c.1042A>G	p.Ile348Val	missense_variant	Exon 11 of 35	ENST00000642920.2	NP_059129.3	Q8NEV4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYO3A	ENST00000642920.2 link	c.1042A>G	p.Ile348Val	missense_variant	Exon 11 of 35		NM_017433.5	ENSP00000495965.1	Q8NEV4-1
MYO3A	ENST00000543632.5 link	c.1042A>G	p.Ile348Val	missense_variant	Exon 10 of 17	1		ENSP00000445909.1	F5H0U9
MYO3A	ENST00000642197.1 link	n.1246A>G		non_coding_transcript_exon_variant	Exon 11 of 27
MYO3A	ENST00000647478.1 link	n.1042A>G		non_coding_transcript_exon_variant	Exon 10 of 30			ENSP00000493932.1	A0A2R8Y4D5

Frequencies

GnomAD3 genomes

AF:

0.686

AC:

104265

AN:

151950

Hom.:

35943

Cov.:

show subpopulations

Gnomad AFR

AF:

0.682

Gnomad AMI

AF:

0.532

Gnomad AMR

AF:

0.631

Gnomad ASJ

AF:

0.670

Gnomad EAS

AF:

0.623

Gnomad SAS

AF:

0.655

Gnomad FIN

AF:

0.774

Gnomad MID

AF:

0.772

Gnomad NFE

AF:

0.697

Gnomad OTH

AF:

0.686

GnomAD2 exomes

AF:

0.676

AC:

169513

AN:

250758

AF XY:

0.677

show subpopulations

Gnomad AFR exome

AF:

0.675

Gnomad AMR exome

AF:

0.622

Gnomad ASJ exome

AF:

0.670

Gnomad EAS exome

AF:

0.619

Gnomad FIN exome

AF:

0.772

Gnomad NFE exome

AF:

0.696

Gnomad OTH exome

AF:

0.678

GnomAD4 exome

AF:

0.685

AC:

994667

AN:

1451048

Hom.:

342464

Cov.:

AF XY:

0.684

AC XY:

494153

AN XY:

722420

show subpopulations

African (AFR)

AF:

0.685

AC:

22777

AN:

33260

American (AMR)

AF:

0.622

AC:

27765

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.666

AC:

17332

AN:

26014

East Asian (EAS)

AF:

0.620

AC:

24532

AN:

39554

South Asian (SAS)

AF:

0.632

AC:

54323

AN:

85916

European-Finnish (FIN)

AF:

0.767

AC:

40837

AN:

53264

Middle Eastern (MID)

AF:

0.691

AC:

3961

AN:

5736

European-Non Finnish (NFE)

AF:

0.691

AC:

762270

AN:

1102600

Other (OTH)

AF:

0.681

AC:

40870

AN:

60042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

14585

29171

43756

58342

72927

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19278

38556

57834

77112

96390

<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:

0.686

AC:

104353

AN:

152068

Hom.:

35977

Cov.:

AF XY:

0.688

AC XY:

51179

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.683

AC:

28320

AN:

41486

American (AMR)

AF:

0.631

AC:

9642

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.670

AC:

2322

AN:

3464

East Asian (EAS)

AF:

0.623

AC:

3218

AN:

5166

South Asian (SAS)

AF:

0.656

AC:

3159

AN:

4818

European-Finnish (FIN)

AF:

0.774

AC:

8190

AN:

10586

Middle Eastern (MID)

AF:

0.762

AC:

224

AN:

294

European-Non Finnish (NFE)

AF:

0.697

AC:

47351

AN:

67956

Other (OTH)

AF:

0.685

AC:

1443

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1666

3333

4999

6666

8332

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

820

1640

2460

3280

4100

<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:

0.687

Hom.:

136949

Bravo

AF:

0.673

ESP6500AA

AF:

0.680

AC:

2996

ESP6500EA

AF:

0.684

AC:

5881

ExAC

AF:

0.678

AC:

82338

Asia WGS

AF:

0.656

AC:

2281

AN:

3478

EpiCase

AF:

0.692

EpiControl

AF:

0.697

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ile348Val in Exon 11 of MYO3A: This variant is not expected to have clinical sig nificance because it has been identified in 32.5% (1216/3738) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs3824699). -

May 09, 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. -

Autosomal recessive nonsyndromic hearing loss 30

Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.48

CADD

Benign

7.8

(source)

DANN

Benign

0.34

DEOGEN2

Benign

0.13

T;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.27

.;T;T

MetaRNN

Benign

0.0000013

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.83

N;N;.

PhyloP100

2.1

PrimateAI

Benign

0.35

PROVEAN

Benign

0.52

.;N;N

REVEL

Benign

0.11

Sift

Benign

1.0

.;T;T

Sift4G

Benign

0.78

.;T;T

Polyphen

0.0

B;B;B

Vest4

0.065, 0.034

MPC

0.053

ClinPred

0.00051

GERP RS

2.7

Varity_R

0.029

gMVP

0.29

Mutation Taster

=100/0

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