rs2230162

Variant names:

• chr18-3176065-C-T
• rs2230162
• NM_003803.4:c.999G>A

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.999G>A​(p.Gly333Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 1,590,008 control chromosomes in the GnomAD database, including 75,850 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6642 hom., cov: 32)
  • Exomes 𝑓: 0.31 (69208 hom.)
• Consequence: MYOM1 NM_003803.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.828
• Publications: 14 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=-0.34).
• BP6: Variant 18-3176065-C-T is Benign according to our data. Variant chr18-3176065-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 226838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.828 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOM1	NM_003803.4	c.999G>A	p.Gly333Gly	synonymous_variant	Exon 6 of 38	ENST00000356443.9	NP_003794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9	c.999G>A	p.Gly333Gly	synonymous_variant	Exon 6 of 38	1	NM_003803.4	ENSP00000348821.4
MYOM1	ENST00000261606.11	c.999G>A	p.Gly333Gly	synonymous_variant	Exon 6 of 37	1		ENSP00000261606.7

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44648 AN: 151996 Hom.: 6633 Cov.: 32

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.262

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.304

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.229

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.298

GnomAD2 exomes AF: 0.282 AC: 69539 AN: 246366 AF XY: 0.286

Gnomad AFR exome AF: 0.272

Gnomad AMR exome AF: 0.197

Gnomad ASJ exome AF: 0.303

Gnomad EAS exome AF: 0.245

Gnomad FIN exome AF: 0.288

Gnomad NFE exome AF: 0.307

Gnomad OTH exome AF: 0.292

GnomAD4 exome AF: 0.306 AC: 440417 AN: 1437894 Hom.: 69208 Cov.: 30 AF XY: 0.306 AC XY: 219367 AN XY: 716216

African (AFR) AF: 0.266 AC: 8779 AN: 32964

American (AMR) AF: 0.204 AC: 9050 AN: 44354

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 8005 AN: 25878

East Asian (EAS) AF: 0.306 AC: 12074 AN: 39470

South Asian (SAS) AF: 0.298 AC: 25357 AN: 85000

European-Finnish (FIN) AF: 0.296 AC: 15724 AN: 53112

Middle Eastern (MID) AF: 0.229 AC: 1309 AN: 5704

European-Non Finnish (NFE) AF: 0.314 AC: 342331 AN: 1091864

Other (OTH) AF: 0.299 AC: 17788 AN: 59548

GnomAD4 genome AF: 0.294 AC: 44698 AN: 152114 Hom.: 6642 Cov.: 32 AF XY: 0.292 AC XY: 21676 AN XY: 74360

African (AFR) AF: 0.273 AC: 11324 AN: 41480

American (AMR) AF: 0.262 AC: 4006 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 1083 AN: 3468

East Asian (EAS) AF: 0.266 AC: 1376 AN: 5168

South Asian (SAS) AF: 0.304 AC: 1466 AN: 4822

European-Finnish (FIN) AF: 0.296 AC: 3136 AN: 10582

Middle Eastern (MID) AF: 0.226 AC: 66 AN: 292

European-Non Finnish (NFE) AF: 0.314 AC: 21363 AN: 67992

Other (OTH) AF: 0.300 AC: 635 AN: 2114

Alfa AF: 0.304 Hom.: 7716

Bravo AF: 0.288

Asia WGS AF: 0.285 AC: 990 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

May 17, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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

Gly333Gly in exon 6 of MYOM1: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 31.2% (2585/8296) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2230162). -

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. -

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	-0.34
CADD	Benign	7.9
DANN	Benign	0.73
PhyloP100		0.83
Mutation Taster		=100/0	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: rs2230162; hg19: chr18-3176063; COSMIC: COSV55288515;