rs61729833

chr10-26166095-G-Achr10-26166095-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_017433.5(MYO3A):c.3028G>A(p.Glu1010Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00194 in 1,614,100 control chromosomes in the GnomAD database, including 40 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 0.0092 (23 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (17 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 6.24

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005947262).
• BP6: Variant 10-26166095-G-A is Benign according to our data. Variant chr10-26166095-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178466.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00917 (1396/152286) while in subpopulation AFR AF= 0.0308 (1280/41546). AF 95% confidence interval is 0.0294. There are 23 homozygotes in gnomad4. There are 643 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 23 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO3A	NM_017433.5	c.3028G>A	p.Glu1010Lys	missense_variant	27/35	ENST00000642920.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO3A	ENST00000642920.2	c.3028G>A	p.Glu1010Lys	missense_variant	27/35		NM_017433.5	P1

Frequencies

GnomAD3 genomes AF: 0.00911 AC: 1387 AN: 152168 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.0307

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00485

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00247 AC: 620 AN: 251400 Hom.: 6 AF XY: 0.00181 AC XY: 246 AN XY: 135872

Gnomad AFR exome AF: 0.0311

Gnomad AMR exome AF: 0.00200

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: 0.000308

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00119 AC: 1737 AN: 1461814 Hom.: 17 Cov.: 30 AF XY: 0.00104 AC XY: 757 AN XY: 727206

Gnomad4 AFR exome AF: 0.0325

Gnomad4 AMR exome AF: 0.00239

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000311

Gnomad4 OTH exome AF: 0.00273

GnomAD4 genome AF: 0.00917 AC: 1396 AN: 152286 Hom.: 23 Cov.: 33 AF XY: 0.00863 AC XY: 643 AN XY: 74478

Gnomad4 AFR AF: 0.0308

Gnomad4 AMR AF: 0.00484

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00176 Hom.: 3

Bravo AF: 0.0107

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0309 AC: 136

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00304 AC: 369

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2018	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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Glu1010Lys in Exon 27 of MYO3A: This variant is not expected to have clinical si gnificance because it has been identified in 2.9% (109/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs61729833). -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 25, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	- -

Autosomal recessive nonsyndromic hearing loss 30 Uncertain:1

Uncertain significance, 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, 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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.97	D
MetaRNN	Benign	0.0059	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.040	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.44	T
Polyphen		0.93	P;P
Vest4		0.46
MVP		0.81
MPC		0.097
ClinPred		0.058	T
GERP RS		6.1
Varity_R		0.48
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: rs61729833; hg19: chr10-26455024; COSMIC: COSV56344629;