rs1962519

Positions:

Variant summary

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

The NM_003803.4(MYOM1):c.541T>C(p.Ser181Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 1,612,490 control chromosomes in the GnomAD database, including 155,065 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 12112 hom., cov: 28)

Exomes 𝑓: 0.43 ( 142953 hom. )

Consequence

MYOM1
NM_003803.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.196

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=9.0599656E-7).

BP6

Variant 18-3188978-A-G is Benign according to our data. Variant chr18-3188978-A-G is described in ClinVar as [Benign]. Clinvar id is 226830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.801 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.541T>C	p.Ser181Pro	missense_variant	4/38	ENST00000356443.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM1	ENST00000356443.9 linkuse as main transcript	c.541T>C	p.Ser181Pro	missense_variant	4/38	1	NM_003803.4	P2	P52179-1
MYOM1	ENST00000261606.11 linkuse as main transcript	c.541T>C	p.Ser181Pro	missense_variant	4/37	1		A2	P52179-2

Frequencies

GnomAD3 genomes

AF:

0.378

AC:

56923

AN:

150678

Hom.:

12103

Cov.:

show subpopulations

Gnomad AFR

AF:

0.205

Gnomad AMI

AF:

0.458

Gnomad AMR

AF:

0.392

Gnomad ASJ

AF:

0.395

Gnomad EAS

AF:

0.821

Gnomad SAS

AF:

0.481

Gnomad FIN

AF:

0.490

Gnomad MID

AF:

0.212

Gnomad NFE

AF:

0.420

Gnomad OTH

AF:

0.374

GnomAD3 exomes

AF:

0.444

AC:

110640

AN:

249218

Hom.:

26642

AF XY:

0.447

AC XY:

60471

AN XY:

135206

show subpopulations

Gnomad AFR exome

AF:

0.197

Gnomad AMR exome

AF:

0.400

Gnomad ASJ exome

AF:

0.392

Gnomad EAS exome

AF:

0.821

Gnomad SAS exome

AF:

0.475

Gnomad FIN exome

AF:

0.504

Gnomad NFE exome

AF:

0.417

Gnomad OTH exome

AF:

0.423

GnomAD4 exome

AF:

0.435

AC:

635354

AN:

1461694

Hom.:

142953

Cov.:

AF XY:

0.436

AC XY:

316962

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.201

Gnomad4 AMR exome

AF:

0.402

Gnomad4 ASJ exome

AF:

0.392

Gnomad4 EAS exome

AF:

0.832

Gnomad4 SAS exome

AF:

0.473

Gnomad4 FIN exome

AF:

0.502

Gnomad4 NFE exome

AF:

0.425

Gnomad4 OTH exome

AF:

0.433

GnomAD4 genome

AF:

0.378

AC:

56967

AN:

150796

Hom.:

12112

Cov.:

AF XY:

0.383

AC XY:

28128

AN XY:

73532

show subpopulations

Gnomad4 AFR

AF:

0.206

Gnomad4 AMR

AF:

0.392

Gnomad4 ASJ

AF:

0.395

Gnomad4 EAS

AF:

0.822

Gnomad4 SAS

AF:

0.483

Gnomad4 FIN

AF:

0.490

Gnomad4 NFE

AF:

0.420

Gnomad4 OTH

AF:

0.379

Alfa

AF:

0.413

Hom.:

34264

Bravo

AF:

0.361

TwinsUK

AF:

0.405

AC:

1501

ALSPAC

AF:

0.426

AC:

1641

ESP6500AA

AF:

0.187

AC:

747

ESP6500EA

AF:

0.415

AC:

3467

ExAC

AF:

0.437

AC:

52817

Asia WGS

AF:

0.614

AC:

2132

AN:

3478

EpiCase

AF:

0.402

EpiControl

AF:

0.392

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 07, 2019	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ser181Pro in exon 4 of MYOM1: This variant is not expected to have clinical sign ificance because it has been identified in 41.5% (3467/8348) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs1962519). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 13, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hypertrophic cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.021

T;.;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.095

LIST_S2

Benign

0.68

T;T;T

MetaRNN

Benign

9.1e-7

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.8

L;.;L

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.3

N;.;N

REVEL

Benign

0.049

Sift

Benign

0.088

T;.;T

Sift4G

Benign

0.20

T;T;T

Polyphen

0.86

P;.;D

Vest4

0.33

MPC

0.18

ClinPred

0.018

GERP RS

1.3

Varity_R

0.25

gMVP

0.061

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