chr10-26174123-C-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM5BP4_StrongBP6BS1BS2

The NM_017433.5(MYO3A):c.3859C>A(p.Pro1287Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,614,124 control chromosomes in the GnomAD database, including 118 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1287R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0081 ( 8 hom., cov: 33)

Exomes 𝑓: 0.011 ( 110 hom. )

Consequence

MYO3A
NM_017433.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.461

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 -11 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-26174124-C-A is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.0032796562).

BP6

Variant 10-26174123-C-A is Benign according to our data. Variant chr10-26174123-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45810.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5}. Variant chr10-26174123-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00814 (1240/152246) while in subpopulation NFE AF= 0.0115 (783/68012). AF 95% confidence interval is 0.0108. There are 8 homozygotes in gnomad4. There are 615 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO3A	NM_017433.5 link	c.3859C>A	p.Pro1287Thr	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.3859C>A	p.Pro1287Thr	missense_variant	Exon 30 of 35		NM_017433.5	ENSP00000495965.1	Q8NEV4-1
MYO3A	ENST00000543632.5 link	c.1777-37720C>A		intron_variant	Intron 16 of 16	1		ENSP00000445909.1	F5H0U9
MYO3A	ENST00000647478.1 link	n.*1393+3584C>A		intron_variant	Intron 27 of 29			ENSP00000493932.1	A0A2R8Y4D5

Frequencies

GnomAD3 genomes

AF:

0.00816

AC:

1241

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00193

Gnomad AMI

AF:

0.0395

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.0190

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0114

Gnomad FIN

AF:

0.0164

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0115

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00929

AC:

2332

AN:

251140

Hom.:

AF XY:

0.0101

AC XY:

1371

AN XY:

135780

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.00266

Gnomad ASJ exome

AF:

0.0163

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0140

Gnomad FIN exome

AF:

0.0172

Gnomad NFE exome

AF:

0.0106

Gnomad OTH exome

AF:

0.00801

GnomAD4 exome

AF:

0.0109

AC:

15993

AN:

1461878

Hom.:

110

Cov.:

AF XY:

0.0111

AC XY:

8102

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00128

Gnomad4 AMR exome

AF:

0.00279

Gnomad4 ASJ exome

AF:

0.0160

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0152

Gnomad4 FIN exome

AF:

0.0159

Gnomad4 NFE exome

AF:

0.0113

Gnomad4 OTH exome

AF:

0.0102

GnomAD4 genome

AF:

0.00814

AC:

1240

AN:

152246

Hom.:

Cov.:

AF XY:

0.00826

AC XY:

615

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.00193

Gnomad4 AMR

AF:

0.00261

Gnomad4 ASJ

AF:

0.0190

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0112

Gnomad4 FIN

AF:

0.0164

Gnomad4 NFE

AF:

0.0115

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.0106

Hom.:

Bravo

AF:

0.00677

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0110

AC:

ExAC

AF:

0.00984

AC:

1195

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0106

EpiControl

AF:

0.00966

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

May 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYO3A: BP4, BS1, BS2 -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pro1287Thr in Exon 30 of MYO3A: This variant is not expected to have clinical si gnificance because it has been identified in 1.0% (72/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs35575696). -

Jul 22, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.22

DEOGEN2

Benign

0.071

T;T

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.66

.;T

MetaRNN

Benign

0.0033

T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.1

L;L

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.97

.;N

REVEL

Benign

0.12

Sift

Benign

0.12

.;T

Sift4G

Benign

0.26

.;T

Polyphen

0.017

B;B

Vest4

0.067

MVP

0.62

MPC

0.097

ClinPred

0.0019

GERP RS

1.8

Varity_R

0.080

gMVP

0.13

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