18-3067274-C-CT

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PM2 PM4 BP6_Very_Strong

The NM_003803.4(MYOM1):c.5045_5046insA(p.Lys1683GlufsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000098 in 1,601,790 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: MYOM1 NM_003803.4 frameshift
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.900

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 1690 codons.
• BP6: Variant 18-3067274-C-CT is Benign according to our data. Variant chr18-3067274-C-CT is described in ClinVar as [Likely_benign]. Clinvar id is 227706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM1	NM_003803.4	c.5045_5046insA	p.Lys1683GlufsTer16	frameshift_variant	38/38	ENST00000356443.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM1	ENST00000356443.9	c.5045_5046insA	p.Lys1683GlufsTer16	frameshift_variant	38/38	1	NM_003803.4	P2
MYOM1	ENST00000261606.11	c.4757_4758insA	p.Lys1587GlufsTer16	frameshift_variant	37/37	1		A2
MYOM1	ENST00000581804.1	n.535_536insA		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000125 AC: 29 AN: 232268 Hom.: 0 AF XY: 0.0000874 AC XY: 11 AN XY: 125910

Gnomad AFR exome AF: 0.00192

Gnomad AMR exome AF: 0.0000612

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000957

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000476 AC: 69 AN: 1449436 Hom.: 0 Cov.: 29 AF XY: 0.0000472 AC XY: 34 AN XY: 719896

Gnomad4 AFR exome AF: 0.00175

Gnomad4 AMR exome AF: 0.0000464

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000361

Gnomad4 OTH exome AF: 0.0000835

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.000617 AC XY: 46 AN XY: 74514

Gnomad4 AFR AF: 0.00204

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000126 Hom.: 0

Bravo AF: 0.000559

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 23, 2015

p.Lys1683fs in exon 38 of MYOM1: This variant is predicted to cause a frameshift within the last exon and is predicted to result in a protein where the last few amino acids are replaced by different residues. This variant is not expected to have clinical significance because it has been identified in 0.3% (15/4502) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broad institute.org; dbSNP rs573184538). -

Hypertrophic cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

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: rs573184538; hg19: chr18-3067272;