rs3824700

chr10-26066977-G-A

Variant summary

Our verdict is Benign. Variant got -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. 13/19 in silico tools predict a benign outcome for this variant. 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:8
• Conservation: PhyloP100: 3.70

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 45823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-26066977-G-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
MYO3A	NM_017433.5	c.956G>A	p.Arg319His	missense_variant, splice_region_variant	11/35	ENST00000642920.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO3A	ENST00000642920.2	c.956G>A	p.Arg319His	missense_variant, splice_region_variant	11/35		NM_017433.5	P1
MYO3A	ENST00000543632.5	c.956G>A	p.Arg319His	missense_variant, splice_region_variant	10/17	1
MYO3A	ENST00000642197.1	n.1160G>A		splice_region_variant, non_coding_transcript_exon_variant	11/27
MYO3A	ENST00000647478.1	c.956G>A	p.Arg319His	missense_variant, splice_region_variant, NMD_transcript_variant	10/30

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

GnomAD3 exomes AF: 0.479 AC: 120193 AN: 251002 Hom.: 30489 AF XY: 0.490 AC XY: 66484 AN XY: 135668

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 SAS exome AF: 0.482

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

Gnomad4 AFR exome AF: 0.357

Gnomad4 AMR exome AF: 0.330

Gnomad4 ASJ exome AF: 0.521

Gnomad4 EAS exome AF: 0.263

Gnomad4 SAS exome AF: 0.482

Gnomad4 FIN exome AF: 0.575

Gnomad4 NFE exome AF: 0.552

Gnomad4 OTH exome AF: 0.515

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

Gnomad4 AFR AF: 0.360

Gnomad4 AMR AF: 0.409

Gnomad4 ASJ AF: 0.534

Gnomad4 EAS AF: 0.272

Gnomad4 SAS AF: 0.494

Gnomad4 FIN AF: 0.580

Gnomad4 NFE AF: 0.555

Gnomad4 OTH AF: 0.479

Alfa AF: 0.530 Hom.: 41742

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	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). -

Autosomal recessive nonsyndromic hearing loss 30 Benign:2

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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
MetaRNN	Benign	0.000059	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-2.6	N;N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.41	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

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

Other links and lift over

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