rs114982270

chr10-26128445-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_017433.5(MYO3A):c.2169T>C(p.Asn723=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000742 in 1,612,832 control chromosomes in the GnomAD database, including 10 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 0.0042 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (6 hom.)
• Consequence: MYO3A NM_017433.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.19

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 10-26128445-T-C is Benign according to our data. Variant chr10-26128445-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45802.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=1.18 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00423 (643/152166) while in subpopulation AFR AF= 0.015 (622/41538). AF 95% confidence interval is 0.014. There are 4 homozygotes in gnomad4. There are 272 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO3A	NM_017433.5	c.2169T>C	p.Asn723=	synonymous_variant	20/35	ENST00000642920.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO3A	ENST00000642920.2	c.2169T>C	p.Asn723=	synonymous_variant	20/35		NM_017433.5	P1
MYO3A	ENST00000543632.5	c.1776+31763T>C		intron_variant		1
MYO3A	ENST00000642197.1	n.2373T>C		non_coding_transcript_exon_variant	20/27
MYO3A	ENST00000647478.1	c.*164T>C		3_prime_UTR_variant, NMD_transcript_variant	18/30

Frequencies

GnomAD3 genomes AF: 0.00420 AC: 639 AN: 152048 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000957 AC: 240 AN: 250886 Hom.: 2 AF XY: 0.000553 AC XY: 75 AN XY: 135582

Gnomad AFR exome AF: 0.0137

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000379 AC: 553 AN: 1460666 Hom.: 6 Cov.: 31 AF XY: 0.000310 AC XY: 225 AN XY: 726722

Gnomad4 AFR exome AF: 0.0143

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.000713

GnomAD4 genome AF: 0.00423 AC: 643 AN: 152166 Hom.: 4 Cov.: 33 AF XY: 0.00366 AC XY: 272 AN XY: 74386

Gnomad4 AFR AF: 0.0150

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00174 Hom.: 2

Bravo AF: 0.00410

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	- -

Autosomal recessive nonsyndromic hearing loss 30 Uncertain:1

Uncertain significance, 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, 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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

Asn723Asn in Exon 20 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 1.5% (56/3736) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs114982270). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	5.5
Dann	Benign	0.67

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: rs114982270; hg19: chr10-26417374;