rs142735495

Positions:

chr18-3188929-G-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.590C>T(p.Thr197Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,612,030 control chromosomes in the GnomAD database, including 33 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.00097 ( 1 hom., cov: 30)

Exomes 𝑓: 0.0014 ( 32 hom. )

Consequence

MYOM1
NM_003803.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.17

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=0.0035447478).

BP6

Variant 18-3188929-G-A is Benign according to our data. Variant chr18-3188929-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-3188929-G-A is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAdExome4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM1	NM_003803.4 linkuse as main transcript	c.590C>T	p.Thr197Met	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.590C>T	p.Thr197Met	missense_variant	4/38	1	NM_003803.4	P2	P52179-1
MYOM1	ENST00000261606.11 linkuse as main transcript	c.590C>T	p.Thr197Met	missense_variant	4/37	1		A2	P52179-2

Frequencies

GnomAD3 genomes

AF:

0.000973

AC:

147

AN:

151138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000976

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00126

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0138

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000648

Gnomad OTH

AF:

0.00288

GnomAD3 exomes

AF:

0.00243

AC:

605

AN:

249230

Hom.:

AF XY:

0.00318

AC XY:

430

AN XY:

135212

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.00407

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.0133

Gnomad FIN exome

AF:

0.000278

Gnomad NFE exome

AF:

0.00108

Gnomad OTH exome

AF:

0.00182

GnomAD4 exome

AF:

0.00142

AC:

2075

AN:

1460774

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

1337

AN XY:

726686

show subpopulations

Gnomad4 AFR exome

AF:

0.0000601

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.00475

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0131

Gnomad4 FIN exome

AF:

0.000243

Gnomad4 NFE exome

AF:

0.000553

Gnomad4 OTH exome

AF:

0.00202

GnomAD4 genome

AF:

0.000972

AC:

147

AN:

151256

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

AN XY:

73856

show subpopulations

Gnomad4 AFR

AF:

0.0000973

Gnomad4 AMR

AF:

0.00126

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0136

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000648

Gnomad4 OTH

AF:

0.00285

Alfa

AF:

0.00118

Hom.:

Bravo

AF:

0.000695

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000835

AC:

ExAC

AF:

0.00246

AC:

297

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00120

EpiControl

AF:

0.00136

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 10, 2015	p.Thr197Met in exon 4 of MYOM1: This variant is not expected to have clinical si gnificance because it has been identified in 1.3% (215/16512) of South Asian chr omosomes, including 4 homozygotes, by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs142735495). -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 27, 2022	This alteration is classified as likely 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. -

Hypertrophic cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.35

DANN

Benign

0.67

DEOGEN2

Benign

0.015

T;.;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0084

LIST_S2

Benign

0.44

T;T;T

MetaRNN

Benign

0.0035

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;.;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

0.51

N;.;N

REVEL

Benign

0.021

Sift

Benign

0.25

T;.;T

Sift4G

Benign

0.11

T;T;T

Polyphen

0.40

B;.;P

Vest4

0.078

MVP

0.35

MPC

0.14

ClinPred

0.010

GERP RS

-1.6

Varity_R

0.014

gMVP

0.16

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