rs2230166

Variant names:

• chr18-3188859-A-G
• rs2230166
• NM_003803.4:c.660T>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.660T>C​(p.Ser220Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0617 in 1,613,030 control chromosomes in the GnomAD database, including 3,965 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (886 hom., cov: 30)
  • Exomes 𝑓: 0.059 (3079 hom.)
• Consequence: MYOM1 NM_003803.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0410
• Publications: 6 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=-0.84).
• BP6: Variant 18-3188859-A-G is Benign according to our data. Variant chr18-3188859-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.041 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOM1	NM_003803.4	c.660T>C	p.Ser220Ser	synonymous_variant	Exon 4 of 38	ENST00000356443.9	NP_003794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9	c.660T>C	p.Ser220Ser	synonymous_variant	Exon 4 of 38	1	NM_003803.4	ENSP00000348821.4
MYOM1	ENST00000261606.11	c.660T>C	p.Ser220Ser	synonymous_variant	Exon 4 of 37	1		ENSP00000261606.7

Frequencies

GnomAD3 genomes AF: 0.0905 AC: 13691 AN: 151304 Hom.: 886 Cov.: 30

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.0653

Gnomad ASJ AF: 0.0953

Gnomad EAS AF: 0.000587

Gnomad SAS AF: 0.0692

Gnomad FIN AF: 0.0300

Gnomad MID AF: 0.0892

Gnomad NFE AF: 0.0550

Gnomad OTH AF: 0.0948

GnomAD2 exomes AF: 0.0579 AC: 14382 AN: 248260 AF XY: 0.0570

Gnomad AFR exome AF: 0.194

Gnomad AMR exome AF: 0.0394

Gnomad ASJ exome AF: 0.0887

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.0301

Gnomad NFE exome AF: 0.0558

Gnomad OTH exome AF: 0.0583

GnomAD4 exome AF: 0.0587 AC: 85801 AN: 1461608 Hom.: 3079 Cov.: 32 AF XY: 0.0583 AC XY: 42398 AN XY: 727092

African (AFR) AF: 0.193 AC: 6450 AN: 33474

American (AMR) AF: 0.0414 AC: 1853 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0901 AC: 2354 AN: 26134

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39700

South Asian (SAS) AF: 0.0627 AC: 5412 AN: 86252

European-Finnish (FIN) AF: 0.0288 AC: 1537 AN: 53402

Middle Eastern (MID) AF: 0.0867 AC: 500 AN: 5768

European-Non Finnish (NFE) AF: 0.0572 AC: 63612 AN: 1111786

Other (OTH) AF: 0.0674 AC: 4071 AN: 60370

GnomAD4 genome AF: 0.0905 AC: 13700 AN: 151422 Hom.: 886 Cov.: 30 AF XY: 0.0890 AC XY: 6583 AN XY: 73950

African (AFR) AF: 0.186 AC: 7673 AN: 41178

American (AMR) AF: 0.0653 AC: 992 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.0953 AC: 330 AN: 3462

East Asian (EAS) AF: 0.000588 AC: 3 AN: 5100

South Asian (SAS) AF: 0.0690 AC: 330 AN: 4780

European-Finnish (FIN) AF: 0.0300 AC: 314 AN: 10480

Middle Eastern (MID) AF: 0.0925 AC: 27 AN: 292

European-Non Finnish (NFE) AF: 0.0550 AC: 3737 AN: 67918

Other (OTH) AF: 0.0938 AC: 197 AN: 2100

Alfa AF: 0.0705 Hom.: 1563

Bravo AF: 0.0979

EpiCase AF: 0.0602

EpiControl AF: 0.0598

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

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

Ser220Ser in exon 4 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 18.4% (744/4036) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs2230166). -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 28, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MYOM1-related disorder Benign:1

Nov 20, 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.6
DANN	Benign	0.30
PhyloP100		0.041
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: rs2230166; hg19: chr18-3188857;