rs72787346

Positions:

• chr10-26088402-C-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.1559C>T​(p.Ala520Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00343 in 1,612,384 control chromosomes in the GnomAD database, including 13 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 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (13 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 7.90

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=0.043385416).
• BP6: Variant 10-26088402-C-T is Benign according to our data. Variant chr10-26088402-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45799.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=1, Uncertain_significance=1}. Variant chr10-26088402-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00207 (316/152306) while in subpopulation NFE AF= 0.0037 (252/68028). AF 95% confidence interval is 0.00333. There are 0 homozygotes in gnomad4. There are 133 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 13 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO3A	NM_017433.5	c.1559C>T	p.Ala520Val	missense_variant	15/35	ENST00000642920.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO3A	ENST00000642920.2	c.1559C>T	p.Ala520Val	missense_variant	15/35		NM_017433.5	P1
MYO3A	ENST00000543632.5	c.1559C>T	p.Ala520Val	missense_variant	14/17	1
MYO3A	ENST00000642197.1	n.1763C>T		non_coding_transcript_exon_variant	15/27
MYO3A	ENST00000647478.1	c.1559C>T	p.Ala520Val	missense_variant, NMD_transcript_variant	14/30

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 316 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00370

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00221 AC: 554 AN: 251114 Hom.: 1 AF XY: 0.00225 AC XY: 306 AN XY: 135778

Gnomad AFR exome AF: 0.000801

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00392

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00357 AC: 5213 AN: 1460078 Hom.: 13 Cov.: 31 AF XY: 0.00344 AC XY: 2496 AN XY: 726506

Gnomad4 AFR exome AF: 0.000419

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000562

Gnomad4 NFE exome AF: 0.00440

Gnomad4 OTH exome AF: 0.00305

GnomAD4 genome AF: 0.00207 AC: 316 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.00179 AC XY: 133 AN XY: 74476

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00370

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00357 Hom.: 2

Bravo AF: 0.00206

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00217 AC: 264

Asia WGS AF: 0.000867 AC: 4 AN: 3474

EpiCase AF: 0.00442

EpiControl AF: 0.00344

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	MYO3A: BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Ala520Val in Exon 15 of MYO3A: This variant is not expected to have clinical sig nificance because it has been identified in 0.4% (27/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs72787346). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 03, 2015	- -

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. -

MYO3A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 14, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.60	D;D;D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.043	T;T;T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.3	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
Polyphen		1.0	D;D;D
Vest4		0.80, 0.77
MVP		0.93
MPC		0.25
ClinPred		0.025	T
GERP RS		5.8
Varity_R		0.68
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs72787346; hg19: chr10-26377331;