18-3142012-C-T

Position:

chr18-3142012-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong

The NM_003803.4(MYOM1):c.1952G>A(p.Arg651Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 1,613,812 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

MYOM1
NM_003803.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.78

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 -10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.009884328).

BP6

Variant 18-3142012-C-T is Benign according to our data. Variant chr18-3142012-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 227693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOM1	NM_003803.4 linkuse as main transcript	c.1952G>A	p.Arg651Gln	missense_variant	14/38	ENST00000356443.9	NP_003794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9 linkuse as main transcript	c.1952G>A	p.Arg651Gln	missense_variant	14/38	1	NM_003803.4	ENSP00000348821	P2	P52179-1
MYOM1	ENST00000261606.11 linkuse as main transcript	c.1952G>A	p.Arg651Gln	missense_variant	14/37	1		ENSP00000261606	A2	P52179-2
MYOM1	ENST00000577294.1 linkuse as main transcript	n.8G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

167

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000429

AC:

107

AN:

249162

Hom.:

AF XY:

0.000333

AC XY:

AN XY:

135186

show subpopulations

Gnomad AFR exome

AF:

0.0000647

Gnomad AMR exome

AF:

0.00293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000443

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000120

AC:

176

AN:

1461622

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

727096

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00322

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.00110

AC:

167

AN:

152190

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

110

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.0107

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.0000370

Hom.:

Bravo

AF:

0.000941

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 09, 2015

p.Arg651Gln in exon 14 of MYOM1: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, >10 mammals have a glutamine (Gln) at this position despite high nearby am ino acid conservation. It has been identified in 0.13% (15/11558) of Latino chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g/; dbSNP rs184721031). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Hypertrophic cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 07, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.032

T;.;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.023

MetaRNN

Benign

0.0099

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.77

N;.;N

MutationTaster

Benign

0.81

N;N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.87

N;.;N

REVEL

Benign

0.036

Sift

Benign

0.043

D;.;T

Sift4G

Benign

0.13

T;T;T

Polyphen

0.061

B;.;B

Vest4

0.20

MVP

0.63

MPC

0.17

ClinPred

0.020

GERP RS

3.1

Varity_R

0.091

gMVP

0.17

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