chr18-3075748-G-A

Variant names:

• chr18-3075748-G-A
• rs1143657
• NM_003803.4:c.4662C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_003803.4(MYOM1):​c.4662C>T​(p.Ala1554Ala) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.13
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
MYOM1	NM_003803.4	c.4662C>T	p.Ala1554Ala	synonymous_variant	Exon 35 of 38	ENST00000356443.9	NP_003794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9	c.4662C>T	p.Ala1554Ala	synonymous_variant	Exon 35 of 38	1	NM_003803.4	ENSP00000348821.4

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27661 AN: 152032 Hom.: 2708 Cov.: 32

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

GnomAD2 exomes AF: 0.178 AC: 39301 AN: 220554 AF XY: 0.176

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 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.: 33 AF XY: 0.171 AC XY: 121152 AN XY: 707350

African (AFR) AF: 0.149 AC: 4848 AN: 32614

American (AMR) AF: 0.147 AC: 6196 AN: 42092

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 5707 AN: 25522

East Asian (EAS) AF: 0.186 AC: 7248 AN: 38968

South Asian (SAS) AF: 0.165 AC: 13799 AN: 83388

European-Finnish (FIN) AF: 0.319 AC: 16608 AN: 52144

Middle Eastern (MID) AF: 0.145 AC: 830 AN: 5714

European-Non Finnish (NFE) AF: 0.164 AC: 177467 AN: 1084216

Other (OTH) AF: 0.179 AC: 10543 AN: 59060

GnomAD4 genome AF: 0.182 AC: 27695 AN: 152150 Hom.: 2717 Cov.: 32 AF XY: 0.190 AC XY: 14113 AN XY: 74340

African (AFR) AF: 0.153 AC: 6368 AN: 41528

American (AMR) AF: 0.161 AC: 2463 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 791 AN: 3468

East Asian (EAS) AF: 0.185 AC: 957 AN: 5184

South Asian (SAS) AF: 0.181 AC: 874 AN: 4824

European-Finnish (FIN) AF: 0.337 AC: 3549 AN: 10540

Middle Eastern (MID) AF: 0.185 AC: 54 AN: 292

European-Non Finnish (NFE) AF: 0.180 AC: 12228 AN: 68004

Other (OTH) AF: 0.157 AC: 332 AN: 2114

Alfa AF: 0.177 Hom.: 1813

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

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 28, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jan 21, 2013

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1143657; hg19: chr18-3075746; COSMIC: COSV55287718; COSMIC: COSV55287718;