rs76382984

Positions:

• chr18-3215133-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003803.4(MYOM1):​c.91C>A​(p.Arg31=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,613,742 control chromosomes in the GnomAD database, including 265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R31R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (25 hom., cov: 32)
  • Exomes 𝑓: 0.015 (240 hom.)
• Consequence: MYOM1 NM_003803.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.56

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 18-3215133-G-T is Benign according to our data. Variant chr18-3215133-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 226836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-3215133-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.56 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0126 (1912/152220) while in subpopulation EAS AF= 0.0416 (215/5166). AF 95% confidence interval is 0.0371. There are 25 homozygotes in gnomad4. There are 990 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM1	NM_003803.4	c.91C>A	p.Arg31=	synonymous_variant	2/38	ENST00000356443.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM1	ENST00000356443.9	c.91C>A	p.Arg31=	synonymous_variant	2/38	1	NM_003803.4	P2
MYOM1	ENST00000261606.11	c.91C>A	p.Arg31=	synonymous_variant	2/37	1		A2
	ENST00000580139.1	n.198-1859G>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1911 AN: 152102 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.00916

Gnomad ASJ AF: 0.0204

Gnomad EAS AF: 0.0413

Gnomad SAS AF: 0.00560

Gnomad FIN AF: 0.0333

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.0101

GnomAD3 exomes AF: 0.0172 AC: 4281 AN: 248290 Hom.: 63 AF XY: 0.0166 AC XY: 2235 AN XY: 134906

Gnomad AFR exome AF: 0.00202

Gnomad AMR exome AF: 0.0131

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.0409

Gnomad SAS exome AF: 0.00619

Gnomad FIN exome AF: 0.0382

Gnomad NFE exome AF: 0.0154

Gnomad OTH exome AF: 0.0171

GnomAD4 exome AF: 0.0152 AC: 22255 AN: 1461522 Hom.: 240 Cov.: 33 AF XY: 0.0150 AC XY: 10894 AN XY: 727052

Gnomad4 AFR exome AF: 0.00170

Gnomad4 AMR exome AF: 0.0132

Gnomad4 ASJ exome AF: 0.0219

Gnomad4 EAS exome AF: 0.0352

Gnomad4 SAS exome AF: 0.00637

Gnomad4 FIN exome AF: 0.0398

Gnomad4 NFE exome AF: 0.0145

Gnomad4 OTH exome AF: 0.0142

GnomAD4 genome AF: 0.0126 AC: 1912 AN: 152220 Hom.: 25 Cov.: 32 AF XY: 0.0133 AC XY: 990 AN XY: 74428

Gnomad4 AFR AF: 0.00205

Gnomad4 AMR AF: 0.00915

Gnomad4 ASJ AF: 0.0204

Gnomad4 EAS AF: 0.0416

Gnomad4 SAS AF: 0.00581

Gnomad4 FIN AF: 0.0333

Gnomad4 NFE AF: 0.0143

Gnomad4 OTH AF: 0.00950

Alfa AF: 0.0136 Hom.: 10

Bravo AF: 0.0107

Asia WGS AF: 0.0210 AC: 72 AN: 3478

EpiCase AF: 0.0133

EpiControl AF: 0.0129

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Arg31Arg in exon 2 of MYOM1: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 1.3% (108/8472) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs76382984). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 10, 2019

- -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	11
DANN	Benign	0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs76382984; hg19: chr18-3215131; COSMIC: COSV55303645;