chr18-3075748-G-A

Position:

chr18-3075748-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_003803.4(MYOM1):c.4662C>T(p.Ala1554=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,575,868 control chromosomes in the GnomAD database, including 25,737 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2717 hom., cov: 32)

Exomes 𝑓: 0.17 ( 23020 hom. )

Consequence

MYOM1
NM_003803.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.13

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 18-3075748-G-A is Benign according to our data. Variant chr18-3075748-G-A is described in ClinVar as [Benign]. Clinvar id is 226825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.13 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.177 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.4662C>T	p.Ala1554=	synonymous_variant	35/38	ENST00000356443.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM1	ENST00000356443.9 linkuse as main transcript	c.4662C>T	p.Ala1554=	synonymous_variant	35/38	1	NM_003803.4	P2	P52179-1
MYOM1	ENST00000261606.11 linkuse as main transcript	c.4374C>T	p.Ala1458=	synonymous_variant	34/37	1		A2	P52179-2
MYOM1	ENST00000581075.1 linkuse as main transcript	c.*308C>T		3_prime_UTR_variant, NMD_transcript_variant	8/8	5

Frequencies

GnomAD3 genomes

AF:

0.182

AC:

27661

AN:

152032

Hom.:

2708

Cov.:

show subpopulations

Gnomad AFR

AF:

0.153

Gnomad AMI

AF:

0.0866

Gnomad AMR

AF:

0.161

Gnomad ASJ

AF:

0.228

Gnomad EAS

AF:

0.185

Gnomad SAS

AF:

0.180

Gnomad FIN

AF:

0.337

Gnomad MID

AF:

0.188

Gnomad NFE

AF:

0.180

Gnomad OTH

AF:

0.153

GnomAD3 exomes

AF:

0.178

AC:

39301

AN:

220554

Hom.:

3744

AF XY:

0.176

AC XY:

20948

AN XY:

118838

show subpopulations

Gnomad AFR exome

AF:

0.150

Gnomad AMR exome

AF:

0.146

Gnomad ASJ exome

AF:

0.219

Gnomad EAS exome

AF:

0.159

Gnomad SAS exome

AF:

0.161

Gnomad FIN exome

AF:

0.321

Gnomad NFE exome

AF:

0.167

Gnomad OTH exome

AF:

0.178

GnomAD4 exome

AF:

0.171

AC:

243246

AN:

1423718

Hom.:

23020

Cov.:

AF XY:

0.171

AC XY:

121152

AN XY:

707350

show subpopulations

Gnomad4 AFR exome

AF:

0.149

Gnomad4 AMR exome

AF:

0.147

Gnomad4 ASJ exome

AF:

0.224

Gnomad4 EAS exome

AF:

0.186

Gnomad4 SAS exome

AF:

0.165

Gnomad4 FIN exome

AF:

0.319

Gnomad4 NFE exome

AF:

0.164

Gnomad4 OTH exome

AF:

0.179

GnomAD4 genome

AF:

0.182

AC:

27695

AN:

152150

Hom.:

2717

Cov.:

AF XY:

0.190

AC XY:

14113

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.153

Gnomad4 AMR

AF:

0.161

Gnomad4 ASJ

AF:

0.228

Gnomad4 EAS

AF:

0.185

Gnomad4 SAS

AF:

0.181

Gnomad4 FIN

AF:

0.337

Gnomad4 NFE

AF:

0.180

Gnomad4 OTH

AF:

0.157

Alfa

AF:

0.177

Hom.:

1623

Bravo

AF:

0.165

Asia WGS

AF:

0.178

AC:

616

AN:

3478

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	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. -
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

Ala1554Ala in exon 35 of MYOM1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 17.0% (1395/8220) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs16944353). -

MYOM1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 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

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 21, 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

BayesDel_noAF

Benign

-0.41

CADD

Benign

7.4

DANN

Benign

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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