rs4759043

Positions:

chr12-57039267-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005379.4(MYO1A):c.1277C>T(p.Pro426Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00745 in 1,613,766 control chromosomes in the GnomAD database, including 1,297 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.012 ( 135 hom., cov: 32)

Exomes 𝑓: 0.0069 ( 1162 hom. )

Consequence

MYO1A
NM_005379.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.71

Variant links:

Genes affected

MYO1A (HGNC:7595): (myosin IA) This gene encodes a member of the myosin superfamily. The protein represents an unconventional myosin; it should not be confused with the conventional skeletal muscle myosin-1 (MYH1). Unconventional myosins contain the basic domains characteristic of conventional myosins and are further distinguished from class members by their tail domains. They function as actin-based molecular motors. Mutations in this gene have been associated with autosomal dominant deafness. Alternatively spliced variants have been found for this gene. [provided by RefSeq, Dec 2011]

MYO1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035052896).

BP6

Variant 12-57039267-G-A is Benign according to our data. Variant chr12-57039267-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 45307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MYO1A	NM_005379.4 linkuse as main transcript	c.1277C>T	p.Pro426Leu	missense_variant	15/28	ENST00000300119.8	NP_005370.1
MYO1A	NM_001256041.2 linkuse as main transcript	c.1277C>T	p.Pro426Leu	missense_variant	16/29		NP_001242970.1
MYO1A	XM_047428876.1 linkuse as main transcript	c.1277C>T	p.Pro426Leu	missense_variant	16/29		XP_047284832.1
MYO1A	XM_011538373.3 linkuse as main transcript	c.1277C>T	p.Pro426Leu	missense_variant	15/25		XP_011536675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MYO1A	ENST00000300119.8 linkuse as main transcript	c.1277C>T	p.Pro426Leu	missense_variant	15/28	1	NM_005379.4	ENSP00000300119	P1
MYO1A	ENST00000442789.6 linkuse as main transcript	c.1277C>T	p.Pro426Leu	missense_variant	16/29	1		ENSP00000393392	P1
MYO1A	ENST00000476795.1 linkuse as main transcript	n.174C>T		non_coding_transcript_exon_variant	1/3	5
MYO1A	ENST00000554234.5 linkuse as main transcript	c.791C>T	p.Pro264Leu	missense_variant, NMD_transcript_variant	11/24	5		ENSP00000451033

Frequencies

GnomAD3 genomes

AF:

0.0122

AC:

1858

AN:

152196

Hom.:

124

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00270

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.107

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00866

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.0225

GnomAD3 exomes

AF:

0.0319

AC:

8006

AN:

251034

Hom.:

989

AF XY:

0.0235

AC XY:

3190

AN XY:

135684

show subpopulations

Gnomad AFR exome

AF:

0.00210

Gnomad AMR exome

AF:

0.220

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00990

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.0264

GnomAD4 exome

AF:

0.00694

AC:

10138

AN:

1461452

Hom.:

1162

Cov.:

AF XY:

0.00575

AC XY:

4184

AN XY:

727054

show subpopulations

Gnomad4 AFR exome

AF:

0.00140

Gnomad4 AMR exome

AF:

0.206

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00967

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000891

Gnomad4 OTH exome

AF:

0.00654

GnomAD4 genome

AF:

0.0123

AC:

1879

AN:

152314

Hom.:

135

Cov.:

AF XY:

0.0128

AC XY:

951

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00269

Gnomad4 AMR

AF:

0.108

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00868

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.0223

Alfa

AF:

0.00397

Hom.:

Bravo

AF:

0.0249

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.0245

AC:

2978

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Pro426Leu in Exon 15 of MYO1A: This variant is not expected to have clinical sig nificance because it has been identified in 15.0% (15/100) of chromosomes from a population in the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP; rs4 759043). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 25, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2017	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. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

D;D

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.88

.;D

MetaRNN

Benign

0.0035

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.6

L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.2

D;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.025

D;D

Sift4G

Uncertain

0.038

D;D

Polyphen

0.98

D;D

Vest4

0.088

MPC

0.088

ClinPred

0.037

GERP RS

3.8

Varity_R

0.19

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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