10-26193231-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_017433.5(MYO3A):c.4465A>G(p.Ile1489Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00637 in 1,613,820 control chromosomes in the GnomAD database, including 49 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0052 ( 4 hom., cov: 31)

Exomes 𝑓: 0.0065 ( 45 hom. )

Consequence

MYO3A
NM_017433.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 0.314

Publications

6 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004360676).

BP6

Variant 10-26193231-A-G is Benign according to our data. Variant chr10-26193231-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45816.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00519 (790/152270) while in subpopulation NFE AF = 0.00626 (426/68024). AF 95% confidence interval is 0.00577. There are 4 homozygotes in GnomAd4. There are 414 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR,SD,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO3A	NM_017433.5 link	c.4465A>G	p.Ile1489Val	missense_variant	Exon 32 of 35	ENST00000642920.2	NP_059129.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MYO3A	ENST00000642920.2 link	c.4465A>G	p.Ile1489Val	missense_variant	Exon 32 of 35		NM_017433.5	ENSP00000495965.1
MYO3A	ENST00000543632.5 link	c.1777-18612A>G		intron_variant	Intron 16 of 16	1		ENSP00000445909.1
MYO3A	ENST00000647478.1 link	n.*1420A>G		non_coding_transcript_exon_variant	Exon 28 of 30			ENSP00000493932.1
MYO3A	ENST00000647478.1 link	n.*1420A>G		3_prime_UTR_variant	Exon 28 of 30			ENSP00000493932.1

Frequencies

GnomAD3 genomes

AF:

0.00519

AC:

790

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.00236

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0224

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00626

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00532

AC:

1337

AN:

251330

AF XY:

0.00544

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00150

Gnomad ASJ exome

AF:

0.00218

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0188

Gnomad NFE exome

AF:

0.00660

Gnomad OTH exome

AF:

0.00700

GnomAD4 exome

AF:

0.00650

AC:

9496

AN:

1461550

Hom.:

Cov.:

AF XY:

0.00639

AC XY:

4643

AN XY:

727086

show subpopulations

African (AFR)

AF:

0.000926

AC:

AN:

33470

American (AMR)

AF:

0.00192

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00249

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00154

AC:

133

AN:

86252

European-Finnish (FIN)

AF:

0.0176

AC:

942

AN:

53410

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00715

AC:

7951

AN:

1111724

Other (OTH)

AF:

0.00475

AC:

287

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

419

838

1256

1675

2094

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

298

596

894

1192

1490

<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:

0.00519

AC:

790

AN:

152270

Hom.:

Cov.:

AF XY:

0.00556

AC XY:

414

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00130

AC:

AN:

41560

American (AMR)

AF:

0.00235

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00104

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.0224

AC:

238

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00626

AC:

426

AN:

68024

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

124

166

207

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00535

Hom.:

Bravo

AF:

0.00414

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00581

AC:

ExAC

AF:

0.00541

AC:

657

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00474

EpiControl

AF:

0.00510

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYO3A: BP4, BS2

Jun 26, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 25, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autosomal recessive nonsyndromic hearing loss 30

Uncertain:1Benign:1

Oct 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

not specified

Benign:2

Jan 21, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ile1489Val in Exon 32 of MYO3A: This variant is not expected to have clinical si gnificance because it has been identified in 0.6% (50/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs147376000).

PreventionGenetics, part of Exact Sciences

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

0.077

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

9.7

(source)

DANN

Benign

0.44

DEOGEN2

Benign

0.063

T;T

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.0

.;T

MetaRNN

Benign

0.0044

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.9

M;M

PhyloP100

0.31

PrimateAI

Benign

0.45

PROVEAN

Benign

0.0

.;N

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;T

Sift4G

Pathogenic

0.0

.;T

Vest4

0.0

ClinPred

0.0079

GERP RS

2.0

Varity_R

0.042

gMVP

0.028

Mutation Taster

=99/1

polymorphism

(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