18-3215158-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003803.4(MYOM1):c.66G>C(p.Val22=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0968 in 1,613,430 control chromosomes in the GnomAD database, including 7,946 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V22V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.10 (847 hom., cov: 32)
  • Exomes 𝑓: 0.096 (7099 hom.)
• Consequence: MYOM1 NM_003803.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.37

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=-0.9).
• BP6: Variant 18-3215158-C-G is Benign according to our data. Variant chr18-3215158-C-G is described in ClinVar as [Benign]. Clinvar id is 226835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM1	NM_003803.4	c.66G>C	p.Val22=	synonymous_variant	2/38	ENST00000356443.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM1	ENST00000356443.9	c.66G>C	p.Val22=	synonymous_variant	2/38	1	NM_003803.4	P2
MYOM1	ENST00000261606.11	c.66G>C	p.Val22=	synonymous_variant	2/37	1		A2
	ENST00000580139.1	n.198-1834C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15733 AN: 152070 Hom.: 849 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.0928

Gnomad ASJ AF: 0.0816

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.0924

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0898

Gnomad OTH AF: 0.0842

GnomAD3 exomes AF: 0.0991 AC: 24525 AN: 247512 Hom.: 1310 AF XY: 0.0989 AC XY: 13297 AN XY: 134466

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.0724

Gnomad ASJ exome AF: 0.0891

Gnomad EAS exome AF: 0.169

Gnomad SAS exome AF: 0.110

Gnomad FIN exome AF: 0.0973

Gnomad NFE exome AF: 0.0917

Gnomad OTH exome AF: 0.0966

GnomAD4 exome AF: 0.0961 AC: 140397 AN: 1461242 Hom.: 7099 Cov.: 33 AF XY: 0.0963 AC XY: 70015 AN XY: 726872

Gnomad4 AFR exome AF: 0.117

Gnomad4 AMR exome AF: 0.0727

Gnomad4 ASJ exome AF: 0.0931

Gnomad4 EAS exome AF: 0.183

Gnomad4 SAS exome AF: 0.111

Gnomad4 FIN exome AF: 0.100

Gnomad4 NFE exome AF: 0.0919

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome AF: 0.103 AC: 15736 AN: 152188 Hom.: 847 Cov.: 32 AF XY: 0.104 AC XY: 7729 AN XY: 74422

Gnomad4 AFR AF: 0.123

Gnomad4 AMR AF: 0.0929

Gnomad4 ASJ AF: 0.0816

Gnomad4 EAS AF: 0.177

Gnomad4 SAS AF: 0.120

Gnomad4 FIN AF: 0.0924

Gnomad4 NFE AF: 0.0897

Gnomad4 OTH AF: 0.0819

Alfa AF: 0.0757 Hom.: 166

Bravo AF: 0.103

Asia WGS AF: 0.154 AC: 536 AN: 3478

EpiCase AF: 0.0860

EpiControl AF: 0.0856

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Val22Val 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 12.0% (504/4212) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs1662316). -

MYOM1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 06, 2018

- -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 21, 2013

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.17
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1662316; hg19: chr18-3215156; COSMIC: COSV55292855;