rs16944353

chr18-3075748-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.13

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]

ACMG classification

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	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	c.4662C>T	p.Ala1554=	synonymous_variant	35/38	1	NM_003803.4	P2
MYOM1	ENST00000261606.11	c.4374C>T	p.Ala1458=	synonymous_variant	34/37	1		A2
MYOM1	ENST00000581075.1	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.: 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

GnomAD3 exomes AF: 0.178 AC: 39301 AN: 220554 Hom.: 3744 AF XY: 0.176 AC XY: 20948 AN XY: 118838

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

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.: 32 AF XY: 0.190 AC XY: 14113 AN XY: 74340

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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, criteria provided, single submitter

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). -

not provided Benign:1

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. -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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

Other links and lift over

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