18-3086067-C-T

Position:

chr18-3086067-C-T

Variant summary

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

The NM_003803.4(MYOM1):c.4222G>A(p.Asp1408Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0769 in 1,607,392 control chromosomes in the GnomAD database, including 5,199 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.056 ( 308 hom., cov: 31)

Exomes 𝑓: 0.079 ( 4891 hom. )

Consequence

MYOM1
NM_003803.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.88

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=0.0024063885).

BP6

Variant 18-3086067-C-T is Benign according to our data. Variant chr18-3086067-C-T is described in ClinVar as [Benign]. Clinvar id is 226822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0772 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOM1	NM_003803.4 linkuse as main transcript	c.4222G>A	p.Asp1408Asn	missense_variant	30/38	ENST00000356443.9	NP_003794.3	P52179-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYOM1	ENST00000356443.9 linkuse as main transcript	c.4222G>A	p.Asp1408Asn	missense_variant	30/38	1	NM_003803.4	ENSP00000348821.4	P52179-1
MYOM1	ENST00000261606.11 linkuse as main transcript	c.3934G>A	p.Asp1312Asn	missense_variant	29/37	1		ENSP00000261606.7	P52179-2
MYOM1	ENST00000581075.1 linkuse as main transcript	n.322G>A		non_coding_transcript_exon_variant	4/8	5		ENSP00000462039.1	J3KRK2

Frequencies

GnomAD3 genomes

AF:

0.0557

AC:

8472

AN:

152144

Hom.:

308

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0132

Gnomad AMI

AF:

0.0516

Gnomad AMR

AF:

0.0617

Gnomad ASJ

AF:

0.0257

Gnomad EAS

AF:

0.0569

Gnomad SAS

AF:

0.0829

Gnomad FIN

AF:

0.0631

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0789

Gnomad OTH

AF:

0.0474

GnomAD3 exomes

AF:

0.0710

AC:

17568

AN:

247318

Hom.:

763

AF XY:

0.0725

AC XY:

9733

AN XY:

134320

show subpopulations

Gnomad AFR exome

AF:

0.0123

Gnomad AMR exome

AF:

0.0772

Gnomad ASJ exome

AF:

0.0235

Gnomad EAS exome

AF:

0.0464

Gnomad SAS exome

AF:

0.0950

Gnomad FIN exome

AF:

0.0701

Gnomad NFE exome

AF:

0.0793

Gnomad OTH exome

AF:

0.0667

GnomAD4 exome

AF:

0.0791

AC:

115160

AN:

1455130

Hom.:

4891

Cov.:

AF XY:

0.0797

AC XY:

57693

AN XY:

724084

show subpopulations

Gnomad4 AFR exome

AF:

0.0113

Gnomad4 AMR exome

AF:

0.0778

Gnomad4 ASJ exome

AF:

0.0241

Gnomad4 EAS exome

AF:

0.0710

Gnomad4 SAS exome

AF:

0.0933

Gnomad4 FIN exome

AF:

0.0724

Gnomad4 NFE exome

AF:

0.0829

Gnomad4 OTH exome

AF:

0.0677

GnomAD4 genome

AF:

0.0556

AC:

8471

AN:

152262

Hom.:

308

Cov.:

AF XY:

0.0549

AC XY:

4087

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0131

Gnomad4 AMR

AF:

0.0618

Gnomad4 ASJ

AF:

0.0257

Gnomad4 EAS

AF:

0.0573

Gnomad4 SAS

AF:

0.0824

Gnomad4 FIN

AF:

0.0631

Gnomad4 NFE

AF:

0.0789

Gnomad4 OTH

AF:

0.0464

Alfa

AF:

0.0720

Hom.:

1042

Bravo

AF:

0.0531

TwinsUK

AF:

0.0860

AC:

319

ALSPAC

AF:

0.0944

AC:

364

ESP6500AA

AF:

0.0163

AC:

ESP6500EA

AF:

0.0716

AC:

588

ExAC

AF:

0.0727

AC:

8780

Asia WGS

AF:

0.0620

AC:

219

AN:

3478

EpiCase

AF:

0.0722

EpiControl

AF:

0.0719

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Asp1408Asn in exon 30 of MYOM1: This variant is not expected to have clinical si gnificance because it has been identified in 7.2% (588/8212) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs3765623). -

MYOM1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 22, 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

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2013

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

0.25

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.40

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.046

T;.;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.92

D;D;D

MetaRNN

Benign

0.0024

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.7

L;.;.

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.5

N;.;N

REVEL

Benign

0.21

Sift

Benign

0.076

T;.;T

Sift4G

Benign

0.13

T;T;T

Polyphen

0.79

P;.;D

Vest4

0.35

MPC

0.50

ClinPred

0.020

GERP RS

5.6

Varity_R

0.41

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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