rs56147819

Variant names:

• chr10-26128409-G-A
• rs56147819
• NM_017433.5:c.2133G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_017433.5(MYO3A):​c.2133G>A​(p.Leu711Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000599 in 1,613,158 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00099 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (8 hom.)
• Consequence: MYO3A NM_017433.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.34

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 10-26128409-G-A is Benign according to our data. Variant chr10-26128409-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164619.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}. Variant chr10-26128409-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.34 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000985 (150/152272) while in subpopulation EAS AF= 0.00636 (33/5188). AF 95% confidence interval is 0.00514. There are 1 homozygotes in gnomad4. There are 77 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO3A	NM_017433.5	c.2133G>A	p.Leu711Leu	synonymous_variant	Exon 20 of 35	ENST00000642920.2	NP_059129.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO3A	ENST00000642920.2	c.2133G>A	p.Leu711Leu	synonymous_variant	Exon 20 of 35		NM_017433.5	ENSP00000495965.1

Frequencies

GnomAD3 genomes AF: 0.000986 AC: 150 AN: 152154 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00616

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00635

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00159 AC: 400 AN: 250980 Hom.: 2 AF XY: 0.00150 AC XY: 203 AN XY: 135640

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00616

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00561

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000559 AC: 816 AN: 1460886 Hom.: 8 Cov.: 31 AF XY: 0.000578 AC XY: 420 AN XY: 726810

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00765

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00518

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.00118

Gnomad4 NFE exome AF: 0.0000594

Gnomad4 OTH exome AF: 0.000779

GnomAD4 genome AF: 0.000985 AC: 150 AN: 152272 Hom.: 1 Cov.: 33 AF XY: 0.00103 AC XY: 77 AN XY: 74450

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00615

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00636

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000223 Hom.: 0

Bravo AF: 0.00149

Asia WGS AF: 0.00289 AC: 10 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Oct 17, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 21, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leu711Leu in Exon 20 of MYO3A: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 0.65% (75/11534) of L atino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadi nstitute.org; dbSNP rs56147819). -

not provided Benign:2

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 30 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	5.2
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs56147819; hg19: chr10-26417338;