rs34067308

chr10-26021577-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_017433.5(MYO3A):c.660C>T(p.Ala220=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0828 in 1,613,882 control chromosomes in the GnomAD database, including 6,190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (418 hom., cov: 32)
  • Exomes 𝑓: 0.084 (5772 hom.)
• Consequence: MYO3A NM_017433.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0710

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 10-26021577-C-T is Benign according to our data. Variant chr10-26021577-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 45822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-26021577-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.071 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0922 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO3A	NM_017433.5	c.660C>T	p.Ala220=	synonymous_variant	8/35	ENST00000642920.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO3A	ENST00000642920.2	c.660C>T	p.Ala220=	synonymous_variant	8/35		NM_017433.5	P1

Frequencies

GnomAD3 genomes AF: 0.0665 AC: 10111 AN: 152054 Hom.: 417 Cov.: 32

Gnomad AFR AF: 0.0276

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0757

Gnomad ASJ AF: 0.0978

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0290

Gnomad FIN AF: 0.0693

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0942

Gnomad OTH AF: 0.0742

GnomAD3 exomes AF: 0.0675 AC: 16974 AN: 251412 Hom.: 760 AF XY: 0.0684 AC XY: 9298 AN XY: 135866

Gnomad AFR exome AF: 0.0271

Gnomad AMR exome AF: 0.0521

Gnomad ASJ exome AF: 0.0927

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.0320

Gnomad FIN exome AF: 0.0701

Gnomad NFE exome AF: 0.0950

Gnomad OTH exome AF: 0.0797

GnomAD4 exome AF: 0.0845 AC: 123507 AN: 1461710 Hom.: 5772 Cov.: 35 AF XY: 0.0833 AC XY: 60571 AN XY: 727164

Gnomad4 AFR exome AF: 0.0257

Gnomad4 AMR exome AF: 0.0547

Gnomad4 ASJ exome AF: 0.0918

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0330

Gnomad4 FIN exome AF: 0.0736

Gnomad4 NFE exome AF: 0.0953

Gnomad4 OTH exome AF: 0.0786

GnomAD4 genome AF: 0.0665 AC: 10112 AN: 152172 Hom.: 418 Cov.: 32 AF XY: 0.0646 AC XY: 4808 AN XY: 74406

Gnomad4 AFR AF: 0.0276

Gnomad4 AMR AF: 0.0756

Gnomad4 ASJ AF: 0.0978

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.0288

Gnomad4 FIN AF: 0.0693

Gnomad4 NFE AF: 0.0942

Gnomad4 OTH AF: 0.0743

Alfa AF: 0.0845 Hom.: 308

Bravo AF: 0.0666

Asia WGS AF: 0.0310 AC: 110 AN: 3478

EpiCase AF: 0.0929

EpiControl AF: 0.103

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Ala220Ala in Exon 08 of MYO3A: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 9.6% (673/7020) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs34067308). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive nonsyndromic hearing loss 30 Benign:2

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

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
BayesDel_noAF	Benign	-0.34
Cadd	Benign	8.7
Dann	Benign	0.54

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: rs34067308; hg19: chr10-26310506;