rs34918608

chr10-26166161-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017433.5(MYO3A):c.3094G>A(p.Ala1032Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00895 in 1,613,232 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0090 (83 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 5.53

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=0.011166692).
• BP6: Variant 10-26166161-G-A is Benign according to our data. Variant chr10-26166161-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 45806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-26166161-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00802 (1221/152244) while in subpopulation NFE AF= 0.011 (745/68010). AF 95% confidence interval is 0.0103. There are 11 homozygotes in gnomad4. There are 638 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO3A	NM_017433.5	c.3094G>A	p.Ala1032Thr	missense_variant	27/35	ENST00000642920.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO3A	ENST00000642920.2	c.3094G>A	p.Ala1032Thr	missense_variant	27/35		NM_017433.5	P1

Frequencies

GnomAD3 genomes AF: 0.00803 AC: 1221 AN: 152126 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00603

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0266

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00815 AC: 2047 AN: 251272 Hom.: 15 AF XY: 0.00802 AC XY: 1089 AN XY: 135814

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.00615

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.0237

Gnomad NFE exome AF: 0.0111

Gnomad OTH exome AF: 0.00945

GnomAD4 exome AF: 0.00904 AC: 13214 AN: 1460988 Hom.: 83 Cov.: 30 AF XY: 0.00901 AC XY: 6550 AN XY: 726900

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00311

Gnomad4 ASJ exome AF: 0.00589

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00152

Gnomad4 FIN exome AF: 0.0252

Gnomad4 NFE exome AF: 0.00987

Gnomad4 OTH exome AF: 0.00724

GnomAD4 genome AF: 0.00802 AC: 1221 AN: 152244 Hom.: 11 Cov.: 33 AF XY: 0.00857 AC XY: 638 AN XY: 74430

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.00602

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0266

Gnomad4 NFE AF: 0.0110

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00974 Hom.: 15

Bravo AF: 0.00613

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00849 AC: 73

ExAC AF: 0.00847 AC: 1029

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00883

EpiControl AF: 0.00871

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 14, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Ala1032Thr in Exon 27 of MYO3A: This variant is not expected to have clinical si gnificance because it has been identified in 0.8% (56/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs34918608). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive nonsyndromic hearing loss 30 Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 30, 2021	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2018	This variant is associated with the following publications: (PMID: 17344846) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	MYO3A: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Uncertain	0.081	D
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.47	T
Polyphen		0.81	P;P
Vest4		0.38
MVP		0.86
MPC		0.064
ClinPred		0.045	T
GERP RS		5.2
Varity_R		0.19
gMVP		0.31

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: rs34918608; hg19: chr10-26455090; COSMIC: COSV56340951;