10-26202966-A-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_017433.5(MYO3A):c.4589A>T(p.Gln1530Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000377 in 1,613,586 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

MYO3A
NM_017433.5 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 1.82

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0058063865).

BP6

Variant 10-26202966-A-T is Benign according to our data. Variant chr10-26202966-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178472.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00215 (327/152334) while in subpopulation AFR AF= 0.00765 (318/41570). AF 95% confidence interval is 0.00696. There are 2 homozygotes in gnomad4. There are 162 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO3A	NM_017433.5 link	c.4589A>T	p.Gln1530Leu	missense_variant, splice_region_variant	Exon 34 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.4589A>T	p.Gln1530Leu	missense_variant, splice_region_variant	Exon 34 of 35		NM_017433.5	ENSP00000495965.1		Q8NEV4-1

Frequencies

GnomAD3 genomes

AF:

0.00215

AC:

328

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00770

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.0000294

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000561

AC:

141

AN:

251224

Hom.:

AF XY:

0.000434

AC XY:

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.00783

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000192

AC:

281

AN:

1461252

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

117

AN XY:

726920

show subpopulations

Gnomad4 AFR exome

AF:

0.00646

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.000480

GnomAD4 genome

AF:

0.00215

AC:

327

AN:

152334

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

162

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00765

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.00240

ESP6500AA

AF:

0.00999

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000749

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Gln1530Leu in Exon 34 of MYO3A: This variant is not expected to have clinical si gnificance because it has been identified in 1.0% (37/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs147749053). -

Autosomal recessive nonsyndromic hearing loss 30

Uncertain:1

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 provided

Benign:1

Jan 25, 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

0.11

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.083

T;T;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.71

.;T;T

MetaRNN

Benign

0.0058

T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.6

L;L;.

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.96

.;N;.

REVEL

Benign

0.19

Sift

Benign

0.16

.;T;.

Sift4G

Benign

0.48

.;T;.

Polyphen

0.0

B;B;.

Vest4

0.12

MVP

0.83

MPC

0.060

ClinPred

0.017

GERP RS

4.0

Varity_R

0.11

gMVP

0.11

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