chr18-3135694-T-A

Position:

chr18-3135694-T-A

Variant summary

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

The NM_003803.4(MYOM1):c.2062A>T(p.Thr688Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00354 in 1,613,898 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T688M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0036 ( 23 hom. )

Consequence

MYOM1
NM_003803.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 6.21

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010278076).

BP6

Variant 18-3135694-T-A is Benign according to our data. Variant chr18-3135694-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 227694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-3135694-T-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM1	NM_003803.4 linkuse as main transcript	c.2062A>T	p.Thr688Ser	missense_variant	15/38	ENST00000356443.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM1	ENST00000356443.9 linkuse as main transcript	c.2062A>T	p.Thr688Ser	missense_variant	15/38	1	NM_003803.4	P2	P52179-1
MYOM1	ENST00000261606.11 linkuse as main transcript	c.2062A>T	p.Thr688Ser	missense_variant	15/37	1		A2	P52179-2
MYOM1	ENST00000577294.1 linkuse as main transcript	n.118A>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.00264

AC:

402

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00962

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00354

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00298

AC:

742

AN:

249122

Hom.:

AF XY:

0.00287

AC XY:

388

AN XY:

135170

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.000377

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0127

Gnomad NFE exome

AF:

0.00382

Gnomad OTH exome

AF:

0.00298

GnomAD4 exome

AF:

0.00364

AC:

5318

AN:

1461672

Hom.:

Cov.:

AF XY:

0.00359

AC XY:

2608

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.0119

Gnomad4 NFE exome

AF:

0.00404

Gnomad4 OTH exome

AF:

0.00253

GnomAD4 genome

AF:

0.00264

AC:

402

AN:

152226

Hom.:

Cov.:

AF XY:

0.00265

AC XY:

197

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000843

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00962

Gnomad4 NFE

AF:

0.00354

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00305

Hom.:

Bravo

AF:

0.00179

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000511

AC:

ESP6500EA

AF:

0.00241

AC:

ExAC

AF:

0.00270

AC:

327

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00245

EpiControl

AF:

0.00243

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Thr688Ser in exon 15 of MYOM1: This variant is not expected to have clinical sig nificance because it has been identified in 2.7% (5/186) of Finnish chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov /projects/SNP; dbSNP rs188677538). -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 22, 2018	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. -

MYOM1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 28, 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). -

Hypertrophic cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.045

T;.;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

T;T;T

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.5

L;.;L

MutationTaster

Benign

0.99

D;D;N

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.8

N;.;N

REVEL

Benign

0.16

Sift

Uncertain

0.0050

D;.;T

Sift4G

Benign

0.26

T;T;T

Polyphen

0.93

P;.;P

Vest4

0.63

MVP

0.82

MPC

0.49

ClinPred

0.017

GERP RS

5.8

Varity_R

0.33

gMVP

0.32

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