rs11659820

chr18-3164387-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_003803.4(MYOM1):c.1392G>A(p.Arg464=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 1,609,800 control chromosomes in the GnomAD database, including 35,415 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3510 hom., cov: 33)
  • Exomes 𝑓: 0.20 (31905 hom.)
• Consequence: MYOM1 NM_003803.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.573

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 18-3164387-C-T is Benign according to our data. Variant chr18-3164387-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 226800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.573 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM1	NM_003803.4	c.1392G>A	p.Arg464=	synonymous_variant	10/38	ENST00000356443.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM1	ENST00000356443.9	c.1392G>A	p.Arg464=	synonymous_variant	10/38	1	NM_003803.4	P2
MYOM1	ENST00000261606.11	c.1392G>A	p.Arg464=	synonymous_variant	10/37	1		A2

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31880 AN: 152084 Hom.: 3497 Cov.: 33

Gnomad AFR AF: 0.266

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.138

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.216

GnomAD3 exomes AF: 0.180 AC: 43521 AN: 242424 Hom.: 4316 AF XY: 0.181 AC XY: 23739 AN XY: 131434

Gnomad AFR exome AF: 0.264

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.191

Gnomad EAS exome AF: 0.00534

Gnomad SAS exome AF: 0.173

Gnomad FIN exome AF: 0.148

Gnomad NFE exome AF: 0.210

Gnomad OTH exome AF: 0.193

GnomAD4 exome AF: 0.204 AC: 296877 AN: 1457598 Hom.: 31905 Cov.: 33 AF XY: 0.203 AC XY: 147231 AN XY: 724694

Gnomad4 AFR exome AF: 0.270

Gnomad4 AMR exome AF: 0.157

Gnomad4 ASJ exome AF: 0.191

Gnomad4 EAS exome AF: 0.00449

Gnomad4 SAS exome AF: 0.180

Gnomad4 FIN exome AF: 0.149

Gnomad4 NFE exome AF: 0.216

Gnomad4 OTH exome AF: 0.192

GnomAD4 genome AF: 0.210 AC: 31929 AN: 152202 Hom.: 3510 Cov.: 33 AF XY: 0.205 AC XY: 15221 AN XY: 74430

Gnomad4 AFR AF: 0.267

Gnomad4 AMR AF: 0.192

Gnomad4 ASJ AF: 0.197

Gnomad4 EAS AF: 0.00520

Gnomad4 SAS AF: 0.171

Gnomad4 FIN AF: 0.138

Gnomad4 NFE AF: 0.208

Gnomad4 OTH AF: 0.214

Alfa AF: 0.213 Hom.: 1833

Bravo AF: 0.216

Asia WGS AF: 0.102 AC: 357 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Arg464Arg in exon 10 of MYOM1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 25.2% (1026/4068) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs11659820). -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 17, 2022	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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 04, 2018

- -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
Cadd	Benign	8.8
Dann	Benign	0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs11659820; hg19: chr18-3164385; COSMIC: COSV55302241;