rs2230165

Variant names:

Variant summary

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

The NM_003803.4(MYOM1):c.644C>T(p.Thr215Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0584 in 1,612,858 control chromosomes in the GnomAD database, including 3,226 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.075 ( 535 hom., cov: 30)

Exomes 𝑓: 0.057 ( 2691 hom. )

Consequence

MYOM1
NM_003803.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.0990

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=0.001524508).

BP6

Variant 18-3188875-G-A is Benign according to our data. Variant chr18-3188875-G-A is described in ClinVar as [Benign]. Clinvar id is 226832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOM1	NM_003803.4 link	c.644C>T	p.Thr215Met	missense_variant	Exon 4 of 38	ENST00000356443.9	NP_003794.3	P52179-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9 link	c.644C>T	p.Thr215Met	missense_variant	Exon 4 of 38	1	NM_003803.4	ENSP00000348821.4		P52179-1
MYOM1	ENST00000261606.11 link	c.644C>T	p.Thr215Met	missense_variant	Exon 4 of 37	1		ENSP00000261606.7		P52179-2

Frequencies

GnomAD3 genomes

AF:

0.0751

AC:

11357

AN:

151310

Hom.:

538

Cov.:

show subpopulations

Gnomad AFR

AF:

0.135

Gnomad AMI

AF:

0.107

Gnomad AMR

AF:

0.0567

Gnomad ASJ

AF:

0.0950

Gnomad EAS

AF:

0.000781

Gnomad SAS

AF:

0.0668

Gnomad FIN

AF:

0.0301

Gnomad MID

AF:

0.0796

Gnomad NFE

AF:

0.0545

Gnomad OTH

AF:

0.0788

GnomAD3 exomes

AF:

0.0533

AC:

13270

AN:

248848

Hom.:

489

AF XY:

0.0536

AC XY:

7231

AN XY:

134978

show subpopulations

Gnomad AFR exome

AF:

0.138

Gnomad AMR exome

AF:

0.0342

Gnomad ASJ exome

AF:

0.0882

Gnomad EAS exome

AF:

0.000167

Gnomad SAS exome

AF:

0.0609

Gnomad FIN exome

AF:

0.0298

Gnomad NFE exome

AF:

0.0554

Gnomad OTH exome

AF:

0.0530

GnomAD4 exome

AF:

0.0567

AC:

82908

AN:

1461430

Hom.:

2691

Cov.:

AF XY:

0.0565

AC XY:

41104

AN XY:

727008

show subpopulations

Gnomad4 AFR exome

AF:

0.137

Gnomad4 AMR exome

AF:

0.0360

Gnomad4 ASJ exome

AF:

0.0898

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.0626

Gnomad4 FIN exome

AF:

0.0287

Gnomad4 NFE exome

AF:

0.0568

Gnomad4 OTH exome

AF:

0.0630

GnomAD4 genome

AF:

0.0750

AC:

11354

AN:

151428

Hom.:

535

Cov.:

AF XY:

0.0739

AC XY:

5459

AN XY:

73918

show subpopulations

Gnomad4 AFR

AF:

0.135

Gnomad4 AMR

AF:

0.0566

Gnomad4 ASJ

AF:

0.0950

Gnomad4 EAS

AF:

0.000783

Gnomad4 SAS

AF:

0.0669

Gnomad4 FIN

AF:

0.0301

Gnomad4 NFE

AF:

0.0545

Gnomad4 OTH

AF:

0.0780

Alfa

AF:

0.0596

Hom.:

447

Bravo

AF:

0.0799

TwinsUK

AF:

0.0583

AC:

216

ALSPAC

AF:

0.0532

AC:

205

ESP6500AA

AF:

0.130

AC:

531

ESP6500EA

AF:

0.0586

AC:

490

ExAC

AF:

0.0566

AC:

6837

EpiCase

AF:

0.0593

EpiControl

AF:

0.0595

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 28, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Thr215Met in exon 4 of MYOM1: This variant is not expected to have clinical sign ificance because it has been identified in 13.0% (531/4076) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs2230165). -

MYOM1-related disorder

Benign:1

Nov 27, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Hypertrophic cardiomyopathy

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Aug 09, 2012

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Benign

0.28

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.64

CADD

Benign

5.2

DANN

Uncertain

0.98

DEOGEN2

Benign

0.014

T;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.54

T;T;T

MetaRNN

Benign

0.0015

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;.;N

PrimateAI

Benign

0.36

PROVEAN

Benign

0.10

N;.;N

REVEL

Benign

0.015

Sift

Benign

0.13

T;.;T

Sift4G

Benign

0.30

T;T;T

Polyphen

0.90

P;.;B

Vest4

0.11

MPC

0.22

ClinPred

0.0025

Varity_R

0.041

gMVP

0.20

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