rs33947968

Positions:

chr10-26145526-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017433.5(MYO3A):c.2497G>T(p.Ala833Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0765 in 1,591,708 control chromosomes in the GnomAD database, including 5,298 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.061 ( 368 hom., cov: 32)

Exomes 𝑓: 0.078 ( 4930 hom. )

Consequence

MYO3A
NM_017433.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 10.0

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=0.010160327).

BP6

Variant 10-26145526-G-T is Benign according to our data. Variant chr10-26145526-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 45803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-26145526-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0866 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.2497G>T	p.Ala833Ser	missense_variant	22/35	ENST00000642920.2	NP_059129.3	Q8NEV4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO3A	ENST00000642920.2 linkuse as main transcript	c.2497G>T	p.Ala833Ser	missense_variant	22/35		NM_017433.5	ENSP00000495965.1		Q8NEV4-1

Frequencies

GnomAD3 genomes

AF:

0.0611

AC:

9295

AN:

152096

Hom.:

368

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0178

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0744

Gnomad ASJ

AF:

0.0975

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.0276

Gnomad FIN

AF:

0.0689

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0885

Gnomad OTH

AF:

0.0700

GnomAD3 exomes

AF:

0.0637

AC:

15940

AN:

250250

Hom.:

678

AF XY:

0.0646

AC XY:

8745

AN XY:

135286

show subpopulations

Gnomad AFR exome

AF:

0.0178

Gnomad AMR exome

AF:

0.0502

Gnomad ASJ exome

AF:

0.0926

Gnomad EAS exome

AF:

0.000600

Gnomad SAS exome

AF:

0.0298

Gnomad FIN exome

AF:

0.0697

Gnomad NFE exome

AF:

0.0894

Gnomad OTH exome

AF:

0.0773

GnomAD4 exome

AF:

0.0781

AC:

112399

AN:

1439494

Hom.:

4930

Cov.:

AF XY:

0.0770

AC XY:

55262

AN XY:

717456

show subpopulations

Gnomad4 AFR exome

AF:

0.0160

Gnomad4 AMR exome

AF:

0.0527

Gnomad4 ASJ exome

AF:

0.0912

Gnomad4 EAS exome

AF:

0.000303

Gnomad4 SAS exome

AF:

0.0308

Gnomad4 FIN exome

AF:

0.0725

Gnomad4 NFE exome

AF:

0.0878

Gnomad4 OTH exome

AF:

0.0749

GnomAD4 genome

AF:

0.0610

AC:

9291

AN:

152214

Hom.:

368

Cov.:

AF XY:

0.0597

AC XY:

4444

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.0177

Gnomad4 AMR

AF:

0.0744

Gnomad4 ASJ

AF:

0.0975

Gnomad4 EAS

AF:

0.000965

Gnomad4 SAS

AF:

0.0274

Gnomad4 FIN

AF:

0.0689

Gnomad4 NFE

AF:

0.0885

Gnomad4 OTH

AF:

0.0702

Alfa

AF:

0.0808

Hom.:

923

Bravo

AF:

0.0606

TwinsUK

AF:

0.0863

AC:

320

ALSPAC

AF:

0.0926

AC:

357

ESP6500AA

AF:

0.0204

AC:

ESP6500EA

AF:

0.0933

AC:

802

ExAC

AF:

0.0638

AC:

7743

Asia WGS

AF:

0.0300

AC:

107

AN:

3478

EpiCase

AF:

0.0893

EpiControl

AF:

0.0962

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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	Ala833Ser in Exon 22 of MYO3A: This variant is not expected to have clinical sig nificance because it has been identified in 9.0% (631/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs33947968). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 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. -

Autosomal recessive nonsyndromic hearing loss 30

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

.;D

MetaRNN

Benign

0.010

T;T

MetaSVM

Uncertain

-0.18

MutationAssessor

Pathogenic

3.4

M;M

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.0

.;D

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

.;D

Sift4G

Uncertain

0.0070

.;D

Polyphen

1.0

D;D

Vest4

0.33

MPC

0.37

ClinPred

0.061

GERP RS

5.7

Varity_R

0.89

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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