chr18-3151738-T-A

Position:

chr18-3151738-T-A

Variant summary

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

The NM_003803.4(MYOM1):c.1799A>T(p.Glu600Val) variant causes a missense change. The variant allele was found at a frequency of 0.00303 in 1,613,796 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E600K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.016 ( 77 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 46 hom. )

Consequence

MYOM1
NM_003803.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.99

Variant links:

Genes affected

MYOM1 (HGNC:7613): (myomesin 1) The giant protein titin, together with its associated proteins, interconnects the major structure of sarcomeres, the M bands and Z discs. The C-terminal end of the titin string extends into the M line, where it binds tightly to M-band constituents of apparent molecular masses of 190 kD (myomesin 1) and 165 kD (myomesin 2). This protein, myomesin 1, like myomesin 2, titin, and other myofibrillar proteins contains structural modules with strong homology to either fibronectin type III (motif I) or immunoglobulin C2 (motif II) domains. Myomesin 1 and myomesin 2 each have a unique N-terminal region followed by 12 modules of motif I or motif II, in the arrangement II-II-I-I-I-I-I-II-II-II-II-II. The two proteins share 50% sequence identity in this repeat-containing region. The head structure formed by these 2 proteins on one end of the titin string extends into the center of the M band. The integrating structure of the sarcomere arises from muscle-specific members of the superfamily of immunoglobulin-like proteins. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

MYOM1 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=0.0089993775).

BP6

Variant 18-3151738-T-A is Benign according to our data. Variant chr18-3151738-T-A is described in ClinVar as [Benign]. Clinvar id is 226803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM1	NM_003803.4 linkuse as main transcript	c.1799A>T	p.Glu600Val	missense_variant	12/38	ENST00000356443.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM1	ENST00000356443.9 linkuse as main transcript	c.1799A>T	p.Glu600Val	missense_variant	12/38	1	NM_003803.4	P2	P52179-1
MYOM1	ENST00000261606.11 linkuse as main transcript	c.1799A>T	p.Glu600Val	missense_variant	12/37	1		A2	P52179-2

Frequencies

GnomAD3 genomes

AF:

0.0163

AC:

2478

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0558

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00759

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.0163

GnomAD3 exomes

AF:

0.00406

AC:

1012

AN:

249168

Hom.:

AF XY:

0.00301

AC XY:

407

AN XY:

135180

show subpopulations

Gnomad AFR exome

AF:

0.0565

Gnomad AMR exome

AF:

0.00270

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000239

Gnomad OTH exome

AF:

0.00265

GnomAD4 exome

AF:

0.00164

AC:

2400

AN:

1461584

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

1047

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.0553

Gnomad4 AMR exome

AF:

0.00349

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000142

Gnomad4 OTH exome

AF:

0.00369

GnomAD4 genome

AF:

0.0163

AC:

2484

AN:

152212

Hom.:

Cov.:

AF XY:

0.0157

AC XY:

1172

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0557

Gnomad4 AMR

AF:

0.00758

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.0161

Alfa

AF:

0.00261

Hom.:

Bravo

AF:

0.0181

ESP6500AA

AF:

0.0486

AC:

184

ESP6500EA

AF:

0.000242

AC:

ExAC

AF:

0.00496

AC:

599

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Glu600Val in exon 12 of MYOM1: This variant is not expected to have clinical sig nificance because it has been identified in 4.9% (184/3786) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs9807556). -

Hypertrophic cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2013

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

T;.;.

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.81

T;T;T

MetaRNN

Benign

0.0090

T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.4

M;.;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.3

D;.;D

REVEL

Benign

0.23

Sift

Benign

0.061

T;.;D

Sift4G

Uncertain

0.0070

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.71

MVP

0.88

MPC

0.48

ClinPred

0.040

GERP RS

5.1

Varity_R

0.51

gMVP

0.69

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

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