rs143613424

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_005379.4(MYO1A):c.2302C>T(p.Arg768Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00104 in 1,613,788 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

MYO1A
NM_005379.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.60

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MYO1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19470915).

BP6

Variant 12-57036354-G-A is Benign according to our data. Variant chr12-57036354-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 45309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 83 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO1A	NM_005379.4 link	c.2302C>T	p.Arg768Trp	missense_variant	Exon 22 of 28	ENST00000300119.8	NP_005370.1	Q9UBC5
MYO1A	NM_001256041.2 link	c.2302C>T	p.Arg768Trp	missense_variant	Exon 23 of 29		NP_001242970.1	Q9UBC5B2R643
MYO1A	XM_047428876.1 link	c.2302C>T	p.Arg768Trp	missense_variant	Exon 23 of 29		XP_047284832.1
MYO1A	XM_011538373.3 link	c.2302C>T	p.Arg768Trp	missense_variant	Exon 22 of 25		XP_011536675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYO1A	ENST00000300119.8 link	c.2302C>T	p.Arg768Trp	missense_variant	Exon 22 of 28	1	NM_005379.4	ENSP00000300119.3	Q9UBC5
MYO1A	ENST00000442789.6 link	c.2302C>T	p.Arg768Trp	missense_variant	Exon 23 of 29	1		ENSP00000393392.2	Q9UBC5
MYO1A	ENST00000554234.5 link	n.1816C>T		non_coding_transcript_exon_variant	Exon 18 of 24	5		ENSP00000451033.1	G3V342

Frequencies

GnomAD3 genomes

AF:

0.000545

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000941

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000828

AC:

208

AN:

251144

AF XY:

0.000906

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00121

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.00109

AC:

1596

AN:

1461496

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

822

AN XY:

727052

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33470

American (AMR)

AF:

0.000335

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00187

AC:

161

AN:

86224

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00124

AC:

1373

AN:

1111732

Other (OTH)

AF:

0.000547

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

189

283

378

472

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000545

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41560

American (AMR)

AF:

0.000196

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00228

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000941

AC:

AN:

68032

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000955

Hom.:

Bravo

AF:

0.000604

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00105

AC:

128

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.000889

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Dec 22, 2017

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Nov 29, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Arg768Trp in exon 22 of MYO1A: This variant is not expected to have clinical sig nificance because it has been identified in 0.2% (16/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS/; dbSNP rs143613424) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;T

Eigen

Benign

0.016

Eigen_PC

Benign

0.0071

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.91

.;D

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.19

T;T

MetaSVM

Uncertain

0.17

MutationAssessor

Uncertain

2.3

M;M

PhyloP100

3.6

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-4.4

D;D

REVEL

Uncertain

0.58

Sift

Uncertain

0.018

D;D

Sift4G

Uncertain

0.027

D;D

Polyphen

1.0

D;D

Vest4

0.74

MVP

0.89

MPC

0.46

ClinPred

0.22

GERP RS

3.9

Varity_R

0.23

gMVP

0.41

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over