rs2298539

Variant names:

• chr18-3075714-C-A
• rs2298539
• NM_003803.4:c.4685+11G>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 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 -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003803.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOM1	NM_003803.4	MANE Select	c.4685+11G>T		intron	N/A	NP_003794.3
	MYOM1	NM_019856.2		c.4397+11G>T		intron	N/A	NP_062830.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOM1	ENST00000356443.9	TSL:1 MANE Select	c.4685+11G>T		intron	N/A	ENSP00000348821.4
	MYOM1	ENST00000261606.11	TSL:1	c.4397+11G>T		intron	N/A	ENSP00000261606.7
	MYOM1	ENST00000941943.1		c.4649+11G>T		intron	N/A	ENSP00000612002.1

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

GnomAD2 exomes AF: 0.492 AC: 113375 AN: 230572 AF XY: 0.491

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 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

African (AFR) AF: 0.893 AC: 29562 AN: 33118

American (AMR) AF: 0.359 AC: 15346 AN: 42784

Ashkenazi Jewish (ASJ) AF: 0.476 AC: 12242 AN: 25696

East Asian (EAS) AF: 0.510 AC: 20016 AN: 39240

South Asian (SAS) AF: 0.571 AC: 48103 AN: 84300

European-Finnish (FIN) AF: 0.556 AC: 29212 AN: 52538

Middle Eastern (MID) AF: 0.490 AC: 2807 AN: 5724

European-Non Finnish (NFE) AF: 0.459 AC: 502661 AN: 1094612

Other (OTH) AF: 0.502 AC: 29907 AN: 59558

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

African (AFR) AF: 0.876 AC: 36364 AN: 41520

American (AMR) AF: 0.407 AC: 6222 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.482 AC: 1672 AN: 3470

East Asian (EAS) AF: 0.508 AC: 2623 AN: 5164

South Asian (SAS) AF: 0.586 AC: 2826 AN: 4824

European-Finnish (FIN) AF: 0.553 AC: 5822 AN: 10530

Middle Eastern (MID) AF: 0.534 AC: 156 AN: 292

European-Non Finnish (NFE) AF: 0.461 AC: 31303 AN: 67976

Other (OTH) AF: 0.515 AC: 1089 AN: 2114

Alfa AF: 0.484 Hom.: 43800

Bravo AF: 0.582

Asia WGS AF: 0.545 AC: 1897 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	12
DANN	Benign	0.36
PhyloP100		0.030
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2298539; hg19: chr18-3075712; COSMIC: COSV55290609; COSMIC: COSV55290609;