NM_017433.5:c.3850A>T

Variant names:

Variant summary

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

The NM_017433.5(MYO3A):c.3850A>T(p.Thr1284Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 1,613,914 control chromosomes in the GnomAD database, including 146,995 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 12536 hom., cov: 32)

Exomes 𝑓: 0.43 ( 134459 hom. )

Consequence

MYO3A
NM_017433.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0610

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.809597E-4).

BP6

Variant 10-26174114-A-T is Benign according to our data. Variant chr10-26174114-A-T is described in ClinVar as [Benign]. Clinvar id is 45809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-26174114-A-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO3A	NM_017433.5 link	c.3850A>T	p.Thr1284Ser	missense_variant	Exon 30 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.3850A>T	p.Thr1284Ser	missense_variant	Exon 30 of 35		NM_017433.5	ENSP00000495965.1	Q8NEV4-1
MYO3A	ENST00000543632.5 link	c.1777-37729A>T		intron_variant	Intron 16 of 16	1		ENSP00000445909.1	F5H0U9
MYO3A	ENST00000647478.1 link	n.*1393+3575A>T		intron_variant	Intron 27 of 29			ENSP00000493932.1	A0A2R8Y4D5

Frequencies

GnomAD3 genomes

AF:

0.401

AC:

60957

AN:

151974

Hom.:

12535

Cov.:

show subpopulations

Gnomad AFR

AF:

0.332

Gnomad AMI

AF:

0.258

Gnomad AMR

AF:

0.395

Gnomad ASJ

AF:

0.448

Gnomad EAS

AF:

0.333

Gnomad SAS

AF:

0.466

Gnomad FIN

AF:

0.459

Gnomad MID

AF:

0.522

Gnomad NFE

AF:

0.435

Gnomad OTH

AF:

0.412

GnomAD3 exomes

AF:

0.412

AC:

103340

AN:

250968

Hom.:

21655

AF XY:

0.419

AC XY:

56872

AN XY:

135736

show subpopulations

Gnomad AFR exome

AF:

0.327

Gnomad AMR exome

AF:

0.349

Gnomad ASJ exome

AF:

0.447

Gnomad EAS exome

AF:

0.322

Gnomad SAS exome

AF:

0.450

Gnomad FIN exome

AF:

0.465

Gnomad NFE exome

AF:

0.433

Gnomad OTH exome

AF:

0.433

GnomAD4 exome

AF:

0.428

AC:

624988

AN:

1461822

Hom.:

134459

Cov.:

AF XY:

0.429

AC XY:

311934

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.338

Gnomad4 AMR exome

AF:

0.356

Gnomad4 ASJ exome

AF:

0.440

Gnomad4 EAS exome

AF:

0.345

Gnomad4 SAS exome

AF:

0.451

Gnomad4 FIN exome

AF:

0.461

Gnomad4 NFE exome

AF:

0.432

Gnomad4 OTH exome

AF:

0.425

GnomAD4 genome

AF:

0.401

AC:

60969

AN:

152092

Hom.:

12536

Cov.:

AF XY:

0.403

AC XY:

29941

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.332

Gnomad4 AMR

AF:

0.395

Gnomad4 ASJ

AF:

0.448

Gnomad4 EAS

AF:

0.333

Gnomad4 SAS

AF:

0.465

Gnomad4 FIN

AF:

0.459

Gnomad4 NFE

AF:

0.435

Gnomad4 OTH

AF:

0.412

Alfa

AF:

0.431

Hom.:

10639

Bravo

AF:

0.387

TwinsUK

AF:

0.422

AC:

1566

ALSPAC

AF:

0.428

AC:

1648

ESP6500AA

AF:

0.329

AC:

1450

ESP6500EA

AF:

0.430

AC:

3694

ExAC

AF:

0.414

AC:

50240

Asia WGS

AF:

0.403

AC:

1400

AN:

3478

EpiCase

AF:

0.444

EpiControl

AF:

0.446

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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. -

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

Thr1284Ser in Exon 30 of MYO3A: This variant is not expected to have clinical si gnificance because it has been identified in 43.2% (3032/7020) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs3740231). -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.048

DANN

Benign

0.54

DEOGEN2

Benign

0.055

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.34

.;T

MetaRNN

Benign

0.00018

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.23

.;N

REVEL

Benign

0.14

Sift

Benign

0.39

.;T

Sift4G

Benign

0.78

.;T

Polyphen

0.0030

B;B

Vest4

0.0090

MutPred

0.054

Gain of phosphorylation at S1280 (P = 0.1471);Gain of phosphorylation at S1280 (P = 0.1471);

MPC

0.057

ClinPred

0.0075

GERP RS

-3.4

Varity_R

0.036

gMVP

0.066

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