rs143918373

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_017433.5(MYO3A):c.1643C>A(p.Pro548His) variant causes a missense change. The variant allele was found at a frequency of 0.000315 in 1,613,648 control chromosomes in the GnomAD database, including 3 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 0.0012 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 1 hom. )

Consequence

MYO3A
NM_017433.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: 4.64

Variant links:

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]

MYO3A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012907296).

BP6

Variant 10-26096461-C-A is Benign according to our data. Variant chr10-26096461-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178465.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00122 (185/152226) while in subpopulation AFR AF= 0.00363 (151/41556). AF 95% confidence interval is 0.00316. There are 2 homozygotes in gnomad4. There are 83 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO3A	NM_017433.5 linkuse as main transcript	c.1643C>A	p.Pro548His	missense_variant	16/35	ENST00000642920.2	NP_059129.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO3A	ENST00000642920.2 linkuse as main transcript	c.1643C>A	p.Pro548His	missense_variant	16/35		NM_017433.5	ENSP00000495965	P1	Q8NEV4-1
MYO3A	ENST00000543632.5 linkuse as main transcript	c.1643C>A	p.Pro548His	missense_variant	15/17	1		ENSP00000445909
MYO3A	ENST00000642197.1 linkuse as main transcript	n.1847C>A		non_coding_transcript_exon_variant	16/27
MYO3A	ENST00000647478.1 linkuse as main transcript	c.1643C>A	p.Pro548His	missense_variant, NMD_transcript_variant	15/30			ENSP00000493932

Frequencies

GnomAD3 genomes

AF:

0.00120

AC:

183

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00360

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

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:

0.000103

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000419

AC:

105

AN:

250834

Hom.:

AF XY:

0.000265

AC XY:

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.00346

Gnomad AMR exome

AF:

0.000868

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:

0.000141

Gnomad OTH exome

AF:

0.000656

GnomAD4 exome

AF:

0.000222

AC:

324

AN:

1461422

Hom.:

Cov.:

AF XY:

0.000212

AC XY:

154

AN XY:

727018

show subpopulations

Gnomad4 AFR exome

AF:

0.00305

Gnomad4 AMR exome

AF:

0.000850

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000124

Gnomad4 OTH exome

AF:

0.000596

GnomAD4 genome

AF:

0.00122

AC:

185

AN:

152226

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00363

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.00117

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000486

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3476

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 17, 2017	The p.Pro548His variant (rs143918373) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.4 percent in the African population (identified on 95 out of 24,022 chromosomes) and has been reported to the ClinVar database (Variation ID: 178465). The proline at position 548 is highly conserved up to frog considering 11 species (Alamut v2.10) and computational analyses of the effects of the p.Pro548His variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Pro548His variant with certainty. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 04, 2018	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2023

The c.1643C>A (p.P548H) alteration is located in exon 16 (coding exon 14) of the MYO3A gene. This alteration results from a C to A substitution at nucleotide position 1643, causing the proline (P) at amino acid position 548 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

Pro548His in Exon 16 of MYO3A: This variant is not expected to have clinical sig nificance because it has been identified in 0.4% (15/3732) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs143918373). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Uncertain

0.50

D;D;D

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

.;D;D

M_CAP

Benign

0.048

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

1.6

L;L;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.4

.;D;D

REVEL

Uncertain

0.41

Sift

Benign

0.060

.;T;D

Sift4G

Benign

0.17

.;T;T

Polyphen

0.29

B;B;D

Vest4

0.49, 0.46

MVP

0.83

MPC

0.076

ClinPred

0.035

GERP RS

3.3

Varity_R

0.35

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over