rs201033926

Positions:

• chr10-26143460-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017433.5(MYO3A):​c.2275A>T​(p.Asn759Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000578 in 1,612,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (0 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 4.10

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.165425).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO3A	NM_017433.5	c.2275A>T	p.Asn759Tyr	missense_variant	21/35	ENST00000642920.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO3A	ENST00000642920.2	c.2275A>T	p.Asn759Tyr	missense_variant	21/35		NM_017433.5	P1
MYO3A	ENST00000543632.5	c.1776+46778A>T		intron_variant		1
MYO3A	ENST00000642197.1	n.2479A>T		non_coding_transcript_exon_variant	21/27
MYO3A	ENST00000647478.1	c.*270A>T		3_prime_UTR_variant, NMD_transcript_variant	19/30

Frequencies

GnomAD3 genomes AF: 0.000282 AC: 43 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000441

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000251 AC: 63 AN: 251124 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135740

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000484

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000608 AC: 888 AN: 1459762 Hom.: 0 Cov.: 31 AF XY: 0.000595 AC XY: 432 AN XY: 726324

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000744

Gnomad4 OTH exome AF: 0.000928

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74498

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000608 Hom.: 0

Bravo AF: 0.000344

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000491

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 30 Uncertain:3

Uncertain significance, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Feb 09, 2016	- -
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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 19, 2021	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 19, 2023	This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 759 of the MYO3A protein (p.Asn759Tyr). This variant is present in population databases (rs201033926, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with MYO3A-related conditions. ClinVar contains an entry for this variant (Variation ID: 164620). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYO3A protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2021	Identified in a patient with bilateral sensorineural hearing loss who also harbored several other variants in different genes in published literature (Sheppard et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29907799) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 12, 2014

Variant classified as Uncertain Significance - Favor Benign. The p.Asn759Tyr var iant in MYO3A has been identified in three individuals with hearing loss, but no ne of them carries a second variant in the MYO3A gene (LMM unpublished data). Th is variant has also been identified in 0.06% (5/8600) of European American chrom osomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs201033926). Although this variant has been seen in the general populati on, its frequency is not high enough to rule out a pathogenic role. The asparagi ne (Asn) at position 759 is moderately conserved in mammals and evolutionary dis tant species; however, several species of birds and reptiles carry a tyrosine (T yr) at this position, supporting that this change may be tolerated. Additional c omputational prediction tools suggest this variant may not impact the protein. I n summary, while the clinical significance of the p.Asn759Tyr variant is uncerta in, these data suggest that it is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Uncertain	0.44	T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.047
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.34	T
Polyphen		0.025	B;B
Vest4		0.33
MVP		0.82
MPC		0.083
ClinPred		0.054	T
GERP RS		3.7
Varity_R		0.52
gMVP		0.38

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: rs201033926; hg19: chr10-26432389; COSMIC: COSV105058603;