rs12297756

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005379.4(MYO1A):c.1517G>C(p.Cys506Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,614,192 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0072 ( 17 hom., cov: 32)

Exomes 𝑓: 0.00079 ( 8 hom. )

Consequence

MYO1A
NM_005379.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.82

Publications

7 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010234833).

BP6

Variant 12-57038825-C-G is Benign according to our data. Variant chr12-57038825-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 164594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00725 (1104/152306) while in subpopulation AFR AF = 0.0248 (1032/41560). AF 95% confidence interval is 0.0236. There are 17 homozygotes in GnomAd4. There are 528 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1104 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MYO1A	NM_005379.4 link	c.1517G>C	p.Cys506Ser	missense_variant	Exon 16 of 28	ENST00000300119.8	NP_005370.1
MYO1A	NM_001256041.2 link	c.1517G>C	p.Cys506Ser	missense_variant	Exon 17 of 29		NP_001242970.1
MYO1A	XM_047428876.1 link	c.1517G>C	p.Cys506Ser	missense_variant	Exon 17 of 29		XP_047284832.1
MYO1A	XM_011538373.3 link	c.1517G>C	p.Cys506Ser	missense_variant	Exon 16 of 25		XP_011536675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MYO1A	ENST00000300119.8 link	c.1517G>C	p.Cys506Ser	missense_variant	Exon 16 of 28	1	NM_005379.4	ENSP00000300119.3
MYO1A	ENST00000442789.6 link	c.1517G>C	p.Cys506Ser	missense_variant	Exon 17 of 29	1		ENSP00000393392.2
MYO1A	ENST00000476795.1 link	n.414G>C		non_coding_transcript_exon_variant	Exon 2 of 3	5
MYO1A	ENST00000554234.5 link	n.1031G>C		non_coding_transcript_exon_variant	Exon 12 of 24	5		ENSP00000451033.1

Frequencies

GnomAD3 genomes

AF:

0.00724

AC:

1102

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0249

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00366

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:

0.00430

GnomAD2 exomes

AF:

0.00204

AC:

512

AN:

251108

AF XY:

0.00147

show subpopulations

Gnomad AFR exome

AF:

0.0269

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000882

Gnomad OTH exome

AF:

0.000979

GnomAD4 exome

AF:

0.000791

AC:

1157

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000682

AC XY:

496

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0258

AC:

863

AN:

33480

American (AMR)

AF:

0.00188

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00226

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000719

AC:

AN:

1112012

Other (OTH)

AF:

0.00189

AC:

114

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

176

265

353

441

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.00725

AC:

1104

AN:

152306

Hom.:

Cov.:

AF XY:

0.00709

AC XY:

528

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0248

AC:

1032

AN:

41560

American (AMR)

AF:

0.00366

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68030

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

105

158

210

263

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00116

Hom.:

Bravo

AF:

0.00835

ESP6500AA

AF:

0.0202

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00233

AC:

283

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 31, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cys506Ser in Exon 16 of MYO1A: This variant is not expected to have clinical sig nificance because it has been identified in 2.0% (76/3738) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs12297756). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.14

T;T

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.46

.;T

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.22

N;N

PhyloP100

2.8

PrimateAI

Benign

0.30

PROVEAN

Benign

1.0

N;N

REVEL

Benign

0.14

Sift

Benign

0.53

T;T

Sift4G

Benign

0.83

T;T

Polyphen

0.0

B;B

Vest4

0.15

MutPred

0.26

Gain of catalytic residue at C506 (P = 0.0456);Gain of catalytic residue at C506 (P = 0.0456);

MVP

0.49

MPC

0.10

ClinPred

0.015

GERP RS

1.6

Varity_R

0.063

gMVP

0.30

Mutation Taster

=100/0

polymorphism

(source)

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

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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