rs149528866

Positions:

chr18-3135646-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_003803.4(MYOM1):c.2110G>A(p.Glu704Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00602 in 1,613,888 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0064 ( 13 hom., cov: 31)

Exomes 𝑓: 0.0060 ( 58 hom. )

Consequence

MYOM1
NM_003803.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.91

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:

MYOM1 (HGNC:):

MYOM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011583).

BP6

Variant 18-3135646-C-T is Benign according to our data. Variant chr18-3135646-C-T is described in ClinVar as [Benign]. Clinvar id is 226809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-3135646-C-T is described in Lovd as [Likely_pathogenic]. Variant chr18-3135646-C-T is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOM1	NM_003803.4 linkuse as main transcript	c.2110G>A	p.Glu704Lys	missense_variant	15/38	ENST00000356443.9	NP_003794.3	P52179-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYOM1	ENST00000356443.9 linkuse as main transcript	c.2110G>A	p.Glu704Lys	missense_variant	15/38	1	NM_003803.4	ENSP00000348821.4	P52179-1
MYOM1	ENST00000261606.11 linkuse as main transcript	c.2110G>A	p.Glu704Lys	missense_variant	15/37	1		ENSP00000261606.7	P52179-2
MYOM1	ENST00000577294.1 linkuse as main transcript	n.166G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.00640

AC:

974

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.0173

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0353

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00644

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00638

AC:

1589

AN:

249158

Hom.:

AF XY:

0.00621

AC XY:

839

AN XY:

135188

show subpopulations

Gnomad AFR exome

AF:

0.000517

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.0166

Gnomad EAS exome

AF:

0.00184

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0329

Gnomad NFE exome

AF:

0.00512

Gnomad OTH exome

AF:

0.00678

GnomAD4 exome

AF:

0.00598

AC:

8736

AN:

1461676

Hom.:

Cov.:

AF XY:

0.00586

AC XY:

4263

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.00183

Gnomad4 ASJ exome

AF:

0.0161

Gnomad4 EAS exome

AF:

0.000680

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.0341

Gnomad4 NFE exome

AF:

0.00531

Gnomad4 OTH exome

AF:

0.00729

GnomAD4 genome

AF:

0.00640

AC:

974

AN:

152212

Hom.:

Cov.:

AF XY:

0.00735

AC XY:

547

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.000843

Gnomad4 AMR

AF:

0.00321

Gnomad4 ASJ

AF:

0.0173

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0353

Gnomad4 NFE

AF:

0.00644

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.00562

Hom.:

Bravo

AF:

0.00371

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000257

AC:

ESP6500EA

AF:

0.00387

AC:

ExAC

AF:

0.00576

AC:

696

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00540

EpiControl

AF:

0.00362

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Glu704Lys in exon 15 of MYOM1: This variant is not expected to have clinical sig nificance because it has been identified in 3.2% (6/186) of Finnish chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov /projects/SNP; dbSNP rs149528866). -

MYOM1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Hypertrophic cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 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

Uncertain

0.40

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.065

T;.;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.84

L;.;L

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-2.3

N;.;N

REVEL

Uncertain

0.38

Sift

Benign

0.057

T;.;T

Sift4G

Benign

0.21

T;T;T

Polyphen

1.0

D;.;D

Vest4

0.89

MVP

0.89

MPC

0.66

ClinPred

0.055

GERP RS

6.0

Varity_R

0.38

gMVP

0.71

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