rs2230163

Variant names:

• chr18-3173966-G-A
• rs2230163
• NM_003803.4:c.1146C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-3173966-G-A
• chr18-3173966-G-T

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.1146C>T​(p.His382His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 1,609,322 control chromosomes in the GnomAD database, including 82,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8693 hom., cov: 31)
  • Exomes 𝑓: 0.31 (73410 hom.)
• Consequence: MYOM1 NM_003803.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.830
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 18-3173966-G-A is Benign according to our data. Variant chr18-3173966-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.83 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOM1	NM_003803.4	c.1146C>T	p.His382His	synonymous_variant	Exon 8 of 38	ENST00000356443.9	NP_003794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9	c.1146C>T	p.His382His	synonymous_variant	Exon 8 of 38	1	NM_003803.4	ENSP00000348821.4
MYOM1	ENST00000261606.11	c.1146C>T	p.His382His	synonymous_variant	Exon 8 of 37	1		ENSP00000261606.7

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50621 AN: 151654 Hom.: 8667 Cov.: 31

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.324

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.337

GnomAD2 exomes AF: 0.297 AC: 73857 AN: 248884 AF XY: 0.298

Gnomad AFR exome AF: 0.410

Gnomad AMR exome AF: 0.210

Gnomad ASJ exome AF: 0.315

Gnomad EAS exome AF: 0.248

Gnomad FIN exome AF: 0.291

Gnomad NFE exome AF: 0.312

Gnomad OTH exome AF: 0.302

GnomAD4 exome AF: 0.315 AC: 458672 AN: 1457550 Hom.: 73410 Cov.: 35 AF XY: 0.314 AC XY: 227692 AN XY: 725238

African (AFR) AF: 0.411 AC: 13733 AN: 33426

American (AMR) AF: 0.217 AC: 9712 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 8320 AN: 26112

East Asian (EAS) AF: 0.307 AC: 12182 AN: 39678

South Asian (SAS) AF: 0.304 AC: 26151 AN: 86144

European-Finnish (FIN) AF: 0.297 AC: 15876 AN: 53374

Middle Eastern (MID) AF: 0.249 AC: 1434 AN: 5762

European-Non Finnish (NFE) AF: 0.318 AC: 352417 AN: 1108116

Other (OTH) AF: 0.313 AC: 18847 AN: 60242

GnomAD4 genome AF: 0.334 AC: 50698 AN: 151772 Hom.: 8693 Cov.: 31 AF XY: 0.330 AC XY: 24524 AN XY: 74206

African (AFR) AF: 0.408 AC: 16869 AN: 41388

American (AMR) AF: 0.281 AC: 4288 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 1122 AN: 3464

East Asian (EAS) AF: 0.266 AC: 1372 AN: 5160

South Asian (SAS) AF: 0.305 AC: 1469 AN: 4816

European-Finnish (FIN) AF: 0.296 AC: 3119 AN: 10542

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.316 AC: 21428 AN: 67828

Other (OTH) AF: 0.339 AC: 716 AN: 2112

Alfa AF: 0.317 Hom.: 16418

Bravo AF: 0.334

Asia WGS AF: 0.293 AC: 1017 AN: 3478

EpiCase AF: 0.314

EpiControl AF: 0.304

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

His382His in exon 8 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 39.2% (1462/3730) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2230163). -

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	-0.81
CADD	Benign	5.6
DANN	Benign	0.48
PhyloP100		0.83
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2230163; hg19: chr18-3173964; COSMIC: COSV55292399;