rs2230167

Variant names:

• chr18-3168818-G-A
• rs2230167
• NM_003803.4:c.1338C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-3168818-G-A
• chr18-3168818-G-C
• chr18-3168818-G-T

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.1338C>T​(p.Asn446Asn) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,612,432 control chromosomes in the GnomAD database, including 59,073 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (5861 hom., cov: 32)
  • Exomes 𝑓: 0.27 (53212 hom.)
• Consequence: MYOM1 NM_003803.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0006205
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.58
• Publications: 17 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=-0.4).
• BP6: Variant 18-3168818-G-A is Benign according to our data. Variant chr18-3168818-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOM1	NM_003803.4	c.1338C>T	p.Asn446Asn	splice_region_variant, synonymous_variant	Exon 9 of 38	ENST00000356443.9	NP_003794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9	c.1338C>T	p.Asn446Asn	splice_region_variant, synonymous_variant	Exon 9 of 38	1	NM_003803.4	ENSP00000348821.4
MYOM1	ENST00000261606.11	c.1338C>T	p.Asn446Asn	splice_region_variant, synonymous_variant	Exon 9 of 37	1		ENSP00000261606.7

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41969 AN: 151842 Hom.: 5849 Cov.: 32

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.218

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.276

Gnomad EAS AF: 0.285

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.276

GnomAD2 exomes AF: 0.257 AC: 63820 AN: 248584 AF XY: 0.258

Gnomad AFR exome AF: 0.323

Gnomad AMR exome AF: 0.187

Gnomad ASJ exome AF: 0.271

Gnomad EAS exome AF: 0.279

Gnomad FIN exome AF: 0.225

Gnomad NFE exome AF: 0.263

Gnomad OTH exome AF: 0.265

GnomAD4 exome AF: 0.268 AC: 391441 AN: 1460470 Hom.: 53212 Cov.: 33 AF XY: 0.268 AC XY: 194893 AN XY: 726560

African (AFR) AF: 0.322 AC: 10787 AN: 33450

American (AMR) AF: 0.190 AC: 8484 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 7126 AN: 26120

East Asian (EAS) AF: 0.318 AC: 12617 AN: 39668

South Asian (SAS) AF: 0.279 AC: 24092 AN: 86198

European-Finnish (FIN) AF: 0.234 AC: 12512 AN: 53388

Middle Eastern (MID) AF: 0.234 AC: 1348 AN: 5766

European-Non Finnish (NFE) AF: 0.268 AC: 298258 AN: 1110862

Other (OTH) AF: 0.269 AC: 16217 AN: 60332

GnomAD4 genome AF: 0.277 AC: 42025 AN: 151962 Hom.: 5861 Cov.: 32 AF XY: 0.273 AC XY: 20270 AN XY: 74278

African (AFR) AF: 0.322 AC: 13318 AN: 41406

American (AMR) AF: 0.234 AC: 3569 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 958 AN: 3470

East Asian (EAS) AF: 0.285 AC: 1472 AN: 5160

South Asian (SAS) AF: 0.279 AC: 1342 AN: 4812

European-Finnish (FIN) AF: 0.231 AC: 2440 AN: 10546

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.266 AC: 18075 AN: 67986

Other (OTH) AF: 0.279 AC: 588 AN: 2110

Alfa AF: 0.270 Hom.: 19929

Bravo AF: 0.275

Asia WGS AF: 0.283 AC: 984 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. -

Oct 29, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Asn446Asn in exon 9 of MYOM1: This variant is not expected to have clinical si gnificance because it has been identified in 31% (1167/3758) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS/; dbSNP rs2230167). -

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	-0.40
CADD	Benign	13
DANN	Benign	0.93
PhyloP100		2.6
Mutation Taster		=53/47	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00062
dbscSNV1_RF	Benign	0.042
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: rs2230167; hg19: chr18-3168816; COSMIC: COSV55292386;