rs2298539

Positions:

• chr18-3075714-C-A
• chr18-3075714-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003803.4(MYOM1):​c.4685+11G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 1,589,660 control chromosomes in the GnomAD database, including 199,735 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (28410 hom., cov: 33)
  • Exomes 𝑓: 0.48 (171325 hom.)
• Consequence: MYOM1 NM_003803.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0300

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 18-3075714-C-A is Benign according to our data. Variant chr18-3075714-C-A is described in ClinVar as [Benign]. Clinvar id is 226826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOM1	NM_003803.4	c.4685+11G>T		intron_variant		ENST00000356443.9	NP_003794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9	c.4685+11G>T		intron_variant		1	NM_003803.4	ENSP00000348821	P2
MYOM1	ENST00000261606.11	c.4397+11G>T		intron_variant		1		ENSP00000261606	A2
MYOM1	ENST00000581075.1			downstream_gene_variant		5		ENSP00000462039

Frequencies

GnomAD3 genomes AF: 0.582 AC: 88404 AN: 151972 Hom.: 28364 Cov.: 33

Gnomad AFR AF: 0.876

Gnomad AMI AF: 0.469

Gnomad AMR AF: 0.407

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.509

Gnomad SAS AF: 0.586

Gnomad FIN AF: 0.553

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.460

Gnomad OTH AF: 0.517

GnomAD3 exomes AF: 0.492 AC: 113375 AN: 230572 Hom.: 29397 AF XY: 0.491 AC XY: 61116 AN XY: 124470

Gnomad AFR exome AF: 0.883

Gnomad AMR exome AF: 0.344

Gnomad ASJ exome AF: 0.466

Gnomad EAS exome AF: 0.497

Gnomad SAS exome AF: 0.568

Gnomad FIN exome AF: 0.554

Gnomad NFE exome AF: 0.456

Gnomad OTH exome AF: 0.474

GnomAD4 exome AF: 0.480 AC: 689856 AN: 1437570 Hom.: 171325 Cov.: 34 AF XY: 0.481 AC XY: 343684 AN XY: 714240

Gnomad4 AFR exome AF: 0.893

Gnomad4 AMR exome AF: 0.359

Gnomad4 ASJ exome AF: 0.476

Gnomad4 EAS exome AF: 0.510

Gnomad4 SAS exome AF: 0.571

Gnomad4 FIN exome AF: 0.556

Gnomad4 NFE exome AF: 0.459

Gnomad4 OTH exome AF: 0.502

GnomAD4 genome AF: 0.582 AC: 88505 AN: 152090 Hom.: 28410 Cov.: 33 AF XY: 0.582 AC XY: 43223 AN XY: 74322

Gnomad4 AFR AF: 0.876

Gnomad4 AMR AF: 0.407

Gnomad4 ASJ AF: 0.482

Gnomad4 EAS AF: 0.508

Gnomad4 SAS AF: 0.586

Gnomad4 FIN AF: 0.553

Gnomad4 NFE AF: 0.461

Gnomad4 OTH AF: 0.515

Alfa AF: 0.474 Hom.: 29949

Bravo AF: 0.582

Asia WGS AF: 0.545 AC: 1897 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

4685+11G>T in intron 35 of MYOM1: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence. It has been identified in 46.3% (3809/8224) of European American chromoso mes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs .washington.edu/EVS; dbSNP rs2298539). -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	12
DANN	Benign	0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2298539; hg19: chr18-3075712; COSMIC: COSV55290609; COSMIC: COSV55290609;