rs12297756

Positions:

chr12-57038825-C-G

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict 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 0.0072 ( 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

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:

MYO1A (HGNC:):

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=0.010234833).

BP6

Variant 12-57038825-C-G is Benign according to our data. Variant chr12-57038825-C-G is described in ClinVar as [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1104 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO1A	NM_005379.4 linkuse as main transcript	c.1517G>C	p.Cys506Ser	missense_variant	16/28	ENST00000300119.8	NP_005370.1	Q9UBC5
MYO1A	NM_001256041.2 linkuse as main transcript	c.1517G>C	p.Cys506Ser	missense_variant	17/29		NP_001242970.1	Q9UBC5B2R643
MYO1A	XM_047428876.1 linkuse as main transcript	c.1517G>C	p.Cys506Ser	missense_variant	17/29		XP_047284832.1
MYO1A	XM_011538373.3 linkuse as main transcript	c.1517G>C	p.Cys506Ser	missense_variant	16/25		XP_011536675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYO1A	ENST00000300119.8 linkuse as main transcript	c.1517G>C	p.Cys506Ser	missense_variant	16/28	1	NM_005379.4	ENSP00000300119.3	Q9UBC5
MYO1A	ENST00000442789.6 linkuse as main transcript	c.1517G>C	p.Cys506Ser	missense_variant	17/29	1		ENSP00000393392.2	Q9UBC5
MYO1A	ENST00000476795.1 linkuse as main transcript	n.414G>C		non_coding_transcript_exon_variant	2/3	5
MYO1A	ENST00000554234.5 linkuse as main transcript	n.1031G>C		non_coding_transcript_exon_variant	12/24	5		ENSP00000451033.1	G3V342

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

GnomAD3 exomes

AF:

0.00204

AC:

512

AN:

251108

Hom.:

AF XY:

0.00147

AC XY:

200

AN XY:

135706

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 SAS 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

Gnomad4 AFR exome

AF:

0.0258

Gnomad4 AMR exome

AF:

0.00188

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000719

Gnomad4 OTH exome

AF:

0.00189

GnomAD4 genome

AF:

0.00725

AC:

1104

AN:

152306

Hom.:

Cov.:

AF XY:

0.00709

AC XY:

528

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0248

Gnomad4 AMR

AF:

0.00366

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:

0.00426

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

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

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

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

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

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