10-26201286-C-G

Position:

chr10-26201286-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_017433.5(MYO3A):c.4567C>G(p.Arg1523Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000437 in 1,578,922 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 1 hom. )

Consequence

MYO3A
NM_017433.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.94

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28823107).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO3A	NM_017433.5 linkuse as main transcript	c.4567C>G	p.Arg1523Gly	missense_variant	33/35	ENST00000642920.2	NP_059129.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO3A	ENST00000642920.2 linkuse as main transcript	c.4567C>G	p.Arg1523Gly	missense_variant	33/35		NM_017433.5	ENSP00000495965	P1	Q8NEV4-1

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

151744

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000774

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000505

AC:

AN:

237596

Hom.:

AF XY:

0.0000467

AC XY:

AN XY:

128522

show subpopulations

Gnomad AFR exome

AF:

0.000604

Gnomad AMR exome

AF:

0.0000302

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:

0.00000938

Gnomad OTH exome

AF:

0.000171

GnomAD4 exome

AF:

0.0000252

AC:

AN:

1427060

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

710604

show subpopulations

Gnomad4 AFR exome

AF:

0.000888

Gnomad4 AMR exome

AF:

0.0000231

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:

0.00000276

Gnomad4 OTH exome

AF:

0.0000339

GnomAD4 genome

AF:

0.000217

AC:

AN:

151862

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.000772

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.000268

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 04, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1523 of the MYO3A protein (p.Arg1523Gly). This variant is present in population databases (rs727504688, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with MYO3A-related conditions. ClinVar contains an entry for this variant (Variation ID: 179176). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 27, 2017

The p.Arg1523Gly variant in MYO3A has been previously identified by our laborato ry in 2 individuals with hearing loss; however, an alternate explanation of the hearing loss was identified in 1 of these individuals. This variant has also be en identified in 0.07% (16/22738) of African chromosomes by the Genome Aggregati on Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs727504688). Alth ough this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational predi ction tools and conservation analysis suggest that the p.Arg1523Gly variant may impact the protein, though this information is not predictive enough to determin e pathogenicity. In summary, the clinical significance of the p.Arg1523Gly varia nt is uncertain. ACMG/AMP Criteria applied: PP3. -

Autosomal recessive nonsyndromic hearing loss 30

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

The c.4567C>G (p.R1523G) alteration is located in exon 33 (coding exon 31) of the MYO3A gene. This alteration results from a C to G substitution at nucleotide position 4567, causing the arginine (R) at amino acid position 1523 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;T;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.79

.;T;T

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.29

T;T;T

MetaSVM

Uncertain

0.63

MutationAssessor

Uncertain

2.5

M;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-2.3

.;N;.

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

.;D;.

Sift4G

Uncertain

0.028

.;D;.

Polyphen

1.0

D;D;.

Vest4

0.58

MVP

0.90

MPC

0.36

ClinPred

0.22

GERP RS

4.8

Varity_R

0.45

gMVP

0.34

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