rs121909305

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_005379.4(MYO1A):c.277C>T(p.Arg93*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,614,184 control chromosomes in the GnomAD database, including 18 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0024 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 15 hom. )

Consequence

MYO1A
NM_005379.4 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:9

Conservation

PhyloP100: 2.55

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 Likely_benign. Variant got -5 ACMG points.

BP6

Variant 12-57047675-G-A is Benign according to our data. Variant chr12-57047675-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 8146.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=1}. Variant chr12-57047675-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 366 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO1A	NM_005379.4 link	c.277C>T	p.Arg93*	stop_gained	Exon 4 of 28	ENST00000300119.8	NP_005370.1	Q9UBC5
MYO1A	NM_001256041.2 link	c.277C>T	p.Arg93*	stop_gained	Exon 5 of 29		NP_001242970.1	Q9UBC5B2R643
MYO1A	XM_047428876.1 link	c.277C>T	p.Arg93*	stop_gained	Exon 5 of 29		XP_047284832.1
MYO1A	XM_011538373.3 link	c.277C>T	p.Arg93*	stop_gained	Exon 4 of 25		XP_011536675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO1A	ENST00000300119.8 link	c.277C>T	p.Arg93*	stop_gained	Exon 4 of 28	1	NM_005379.4	ENSP00000300119.3		Q9UBC5

Frequencies

GnomAD3 genomes

AF:

0.00240

AC:

366

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000820

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00429

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00290

AC:

727

AN:

250558

Hom.:

AF XY:

0.00292

AC XY:

395

AN XY:

135466

show subpopulations

Gnomad AFR exome

AF:

0.000617

Gnomad AMR exome

AF:

0.00379

Gnomad ASJ exome

AF:

0.00110

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000457

Gnomad FIN exome

AF:

0.00296

Gnomad NFE exome

AF:

0.00413

Gnomad OTH exome

AF:

0.00491

GnomAD4 exome

AF:

0.00376

AC:

5498

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00366

AC XY:

2660

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.00362

Gnomad4 ASJ exome

AF:

0.00122

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000568

Gnomad4 FIN exome

AF:

0.00307

Gnomad4 NFE exome

AF:

0.00438

Gnomad4 OTH exome

AF:

0.00303

GnomAD4 genome

AF:

0.00240

AC:

366

AN:

152322

Hom.:

Cov.:

AF XY:

0.00222

AC XY:

165

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000818

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00123

Gnomad4 NFE

AF:

0.00429

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00381

Hom.:

Bravo

AF:

0.00271

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00523

AC:

ExAC

AF:

0.00320

AC:

389

EpiCase

AF:

0.00453

EpiControl

AF:

0.00344

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:6

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYO1A: BS1 -

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 02, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29308629, 27759032, 25262649, 24616153, 26086970, 12736868, 25525159) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1Benign:1

Apr 12, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Arg93X variant in MYO1A has been reported in 1 Italian individual with moderately-severe sensor ineural hearing loss; however it was also present in this individual?s mother wh o reported normal hearing (Donaudy 2003). It has also been identified in 0.5% (4 5/8600) of European American chromosomes and 0.07% (3/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/), as well as in 0.8% (1/120) of Colombian chromosomes by the 1000 Genomes P roject (dbSNP rs121909305). This nonsense variant leads to a premature terminati on codon at position 93, which is predicted to lead to a truncated or absent pro tein. However, it is unclear whether loss of function variants in MYO1A are caus ative for hearing loss. In summary, although we cannot rule out that this varian t may be causative for dominant hearing loss with low penetrance and/or variable expressivity, based upon its high frequency in the general population and its p resence in an unaffected family member of an individual with hearing loss, we wo uld lean towards a more likely benign role. -

Autosomal dominant nonsyndromic hearing loss 48

Uncertain:1Benign:1

May 10, 2016

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: research

- -

May 01, 2014

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

MYO1A-related disorder

Benign:1

Feb 26, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.35

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.81

Vest4

0.80

GERP RS

1.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.31

Position offset: 46

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