rs35010955

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_017433.5(MYO3A):c.624C>T(p.Asp208=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0851 in 1,613,856 control chromosomes in the GnomAD database, including 6,413 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.078 ( 514 hom., cov: 32)

Exomes 𝑓: 0.086 ( 5899 hom. )

Consequence

MYO3A
NM_017433.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.73

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.25).

BP6

Variant 10-26021541-C-T is Benign according to our data. Variant chr10-26021541-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 45820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-26021541-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=2.73 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0925 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO3A	NM_017433.5 linkuse as main transcript	c.624C>T	p.Asp208=	synonymous_variant	8/35	ENST00000642920.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO3A	ENST00000642920.2 linkuse as main transcript	c.624C>T	p.Asp208=	synonymous_variant	8/35		NM_017433.5	P1	Q8NEV4-1

Frequencies

GnomAD3 genomes

AF:

0.0778

AC:

11837

AN:

152076

Hom.:

511

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0647

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0862

Gnomad ASJ

AF:

0.0978

Gnomad EAS

AF:

0.000962

Gnomad SAS

AF:

0.0290

Gnomad FIN

AF:

0.0692

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0944

Gnomad OTH

AF:

0.0794

GnomAD3 exomes

AF:

0.0707

AC:

17779

AN:

251384

Hom.:

807

AF XY:

0.0709

AC XY:

9631

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.0671

Gnomad AMR exome

AF:

0.0557

Gnomad ASJ exome

AF:

0.0928

Gnomad EAS exome

AF:

0.000598

Gnomad SAS exome

AF:

0.0321

Gnomad FIN exome

AF:

0.0701

Gnomad NFE exome

AF:

0.0952

Gnomad OTH exome

AF:

0.0808

GnomAD4 exome

AF:

0.0859

AC:

125527

AN:

1461662

Hom.:

5899

Cov.:

AF XY:

0.0845

AC XY:

61451

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.0664

Gnomad4 AMR exome

AF:

0.0588

Gnomad4 ASJ exome

AF:

0.0918

Gnomad4 EAS exome

AF:

0.000403

Gnomad4 SAS exome

AF:

0.0332

Gnomad4 FIN exome

AF:

0.0736

Gnomad4 NFE exome

AF:

0.0956

Gnomad4 OTH exome

AF:

0.0815

GnomAD4 genome

AF:

0.0778

AC:

11845

AN:

152194

Hom.:

514

Cov.:

AF XY:

0.0762

AC XY:

5668

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0647

Gnomad4 AMR

AF:

0.0861

Gnomad4 ASJ

AF:

0.0978

Gnomad4 EAS

AF:

0.000964

Gnomad4 SAS

AF:

0.0288

Gnomad4 FIN

AF:

0.0692

Gnomad4 NFE

AF:

0.0944

Gnomad4 OTH

AF:

0.0795

Alfa

AF:

0.0893

Hom.:

321

Bravo

AF:

0.0793

Asia WGS

AF:

0.0340

AC:

120

AN:

3478

EpiCase

AF:

0.0930

EpiControl

AF:

0.103

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	Asp208Asp 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% (677/7020) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs35010955). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

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 12, 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

-0.25

Cadd

Benign

Dann

Benign

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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