chr18-3067280-A-G

Variant names:

• chr18-3067280-A-G
• rs2230164
• NM_003803.4:c.5040T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003803.4(MYOM1):​c.5040T>C​(p.Gly1680Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 1,602,184 control chromosomes in the GnomAD database, including 198,578 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (25704 hom., cov: 32)
  • Exomes 𝑓: 0.48 (172874 hom.)
• Consequence: MYOM1 NM_003803.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.491
• Publications: 18 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 18-3067280-A-G is Benign according to our data. Variant chr18-3067280-A-G is described in ClinVar as [Benign]. Clinvar id is 226828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.491 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOM1	NM_003803.4	c.5040T>C	p.Gly1680Gly	synonymous_variant	Exon 38 of 38	ENST00000356443.9	NP_003794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9	c.5040T>C	p.Gly1680Gly	synonymous_variant	Exon 38 of 38	1	NM_003803.4	ENSP00000348821.4
MYOM1	ENST00000261606.11	c.4752T>C	p.Gly1584Gly	synonymous_variant	Exon 37 of 37	1		ENSP00000261606.7
MYOM1	ENST00000581804.1	n.530T>C		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes AF: 0.562 AC: 85401 AN: 151940 Hom.: 25666 Cov.: 32

Gnomad AFR AF: 0.790

Gnomad AMI AF: 0.470

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.531

Gnomad SAS AF: 0.577

Gnomad FIN AF: 0.585

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.465

Gnomad OTH AF: 0.501

GnomAD2 exomes AF: 0.498 AC: 116783 AN: 234312 AF XY: 0.500

Gnomad AFR exome AF: 0.788

Gnomad AMR exome AF: 0.348

Gnomad ASJ exome AF: 0.464

Gnomad EAS exome AF: 0.529

Gnomad FIN exome AF: 0.589

Gnomad NFE exome AF: 0.469

Gnomad OTH exome AF: 0.479

GnomAD4 exome AF: 0.484 AC: 701689 AN: 1450126 Hom.: 172874 Cov.: 58 AF XY: 0.485 AC XY: 349646 AN XY: 720332

African (AFR) AF: 0.799 AC: 26556 AN: 33216

American (AMR) AF: 0.360 AC: 15562 AN: 43232

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 12156 AN: 25852

East Asian (EAS) AF: 0.540 AC: 21285 AN: 39384

South Asian (SAS) AF: 0.567 AC: 48100 AN: 84870

European-Finnish (FIN) AF: 0.585 AC: 30878 AN: 52744

Middle Eastern (MID) AF: 0.492 AC: 2034 AN: 4136

European-Non Finnish (NFE) AF: 0.465 AC: 515114 AN: 1106808

Other (OTH) AF: 0.501 AC: 30004 AN: 59884

GnomAD4 genome AF: 0.562 AC: 85495 AN: 152058 Hom.: 25704 Cov.: 32 AF XY: 0.564 AC XY: 41922 AN XY: 74316

African (AFR) AF: 0.790 AC: 32813 AN: 41518

American (AMR) AF: 0.400 AC: 6105 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 1640 AN: 3470

East Asian (EAS) AF: 0.530 AC: 2733 AN: 5156

South Asian (SAS) AF: 0.577 AC: 2777 AN: 4810

European-Finnish (FIN) AF: 0.585 AC: 6170 AN: 10552

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.465 AC: 31622 AN: 67974

Other (OTH) AF: 0.500 AC: 1056 AN: 2114

Alfa AF: 0.473 Hom.: 32582

Bravo AF: 0.557

Asia WGS AF: 0.551 AC: 1914 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 07, 2019

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Gly1680Gly in exon 38 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 46.6% (3990/8554) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2230164). -

not provided Benign:2

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hypertrophic cardiomyopathy Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.75
DANN	Benign	0.19
PhyloP100		-0.49
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2230164; hg19: chr18-3067278; COSMIC: COSV55294376;