rs3824700

Variant names:

• chr10-26066977-G-A
• rs3824700
• NM_017433.5:c.956G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-26066977-G-A
• chr10-26066977-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017433.5(MYO3A):​c.956G>A​(p.Arg319His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.522 in 1,599,846 control chromosomes in the GnomAD database, including 223,766 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (17966 hom., cov: 33)
  • Exomes 𝑓: 0.53 (205800 hom.)
• Consequence: MYO3A NM_017433.5 missense, splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.70
• Publications: 34 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 30

  Inheritance: AR, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal dominant 90

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.898216E-5).
• BP6: Variant 10-26066977-G-A is Benign according to our data. Variant chr10-26066977-G-A is described in ClinVar as Benign. ClinVar VariationId is 45823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.551 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO3A	NM_017433.5	c.956G>A	p.Arg319His	missense_variant, splice_region_variant	Exon 11 of 35	ENST00000642920.2	NP_059129.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO3A	ENST00000642920.2	c.956G>A	p.Arg319His	missense_variant, splice_region_variant	Exon 11 of 35		NM_017433.5	ENSP00000495965.1
MYO3A	ENST00000543632.5	c.956G>A	p.Arg319His	missense_variant, splice_region_variant	Exon 10 of 17	1		ENSP00000445909.1
MYO3A	ENST00000642197.1	n.1160G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 11 of 27
MYO3A	ENST00000647478.1	n.956G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 10 of 30			ENSP00000493932.1

Frequencies

GnomAD3 genomes AF: 0.475 AC: 72235 AN: 151918 Hom.: 17961 Cov.: 33

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.432

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.271

Gnomad SAS AF: 0.495

Gnomad FIN AF: 0.580

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.555

Gnomad OTH AF: 0.478

GnomAD2 exomes AF: 0.479 AC: 120193 AN: 251002 AF XY: 0.490

Gnomad AFR exome AF: 0.353

Gnomad AMR exome AF: 0.319

Gnomad ASJ exome AF: 0.528

Gnomad EAS exome AF: 0.272

Gnomad FIN exome AF: 0.579

Gnomad NFE exome AF: 0.554

Gnomad OTH exome AF: 0.504

GnomAD4 exome AF: 0.527 AC: 763105 AN: 1447810 Hom.: 205800 Cov.: 31 AF XY: 0.527 AC XY: 380281 AN XY: 721052

African (AFR) AF: 0.357 AC: 11865 AN: 33224

American (AMR) AF: 0.330 AC: 14763 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 13572 AN: 26042

East Asian (EAS) AF: 0.263 AC: 10384 AN: 39554

South Asian (SAS) AF: 0.482 AC: 41461 AN: 85976

European-Finnish (FIN) AF: 0.575 AC: 30650 AN: 53262

Middle Eastern (MID) AF: 0.556 AC: 3191 AN: 5736

European-Non Finnish (NFE) AF: 0.552 AC: 606408 AN: 1099470

Other (OTH) AF: 0.515 AC: 30811 AN: 59874

GnomAD4 genome AF: 0.475 AC: 72253 AN: 152036 Hom.: 17966 Cov.: 33 AF XY: 0.475 AC XY: 35278 AN XY: 74294

African (AFR) AF: 0.360 AC: 14921 AN: 41466

American (AMR) AF: 0.409 AC: 6252 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1854 AN: 3470

East Asian (EAS) AF: 0.272 AC: 1401 AN: 5158

South Asian (SAS) AF: 0.494 AC: 2375 AN: 4810

European-Finnish (FIN) AF: 0.580 AC: 6127 AN: 10558

Middle Eastern (MID) AF: 0.592 AC: 173 AN: 292

European-Non Finnish (NFE) AF: 0.555 AC: 37748 AN: 67984

Other (OTH) AF: 0.479 AC: 1009 AN: 2108

Alfa AF: 0.523 Hom.: 92290

Bravo AF: 0.451

TwinsUK AF: 0.545 AC: 2020

ALSPAC AF: 0.542 AC: 2090

ESP6500AA AF: 0.368 AC: 1621

ESP6500EA AF: 0.550 AC: 4731

ExAC AF: 0.485 AC: 58845

Asia WGS AF: 0.397 AC: 1382 AN: 3478

EpiCase AF: 0.556

EpiControl AF: 0.561

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arg319His in Exon 11 of MYO3A: This variant is not expected to have clinical sig nificance because it has been identified in 45.0% (3157/7020) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs3824700). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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 13, 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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 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	0.058
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Benign	0.15
DEOGEN2	Benign	0.035	T;T;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.14	.;T;T
MetaRNN	Benign	0.000059	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-2.6	N;N;.
PhyloP100		3.7
PrimateAI	Benign	0.41	T
PROVEAN	Benign	4.2	.;N;N
REVEL	Uncertain	0.30
Sift	Benign	1.0	.;T;T
Sift4G	Benign	1.0	.;T;T
Polyphen		0.0	B;B;B
Vest4		0.082, 0.043
MPC		0.074
ClinPred		0.014	T
GERP RS		5.6
Varity_R		0.051
gMVP		0.25
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3824700; hg19: chr10-26355906; COSMIC: COSV56320753;