rs554705715

Positions:

• chr18-3164452-TA-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_003803.4(MYOM1):​c.1340-14del variant causes a splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.00361 in 1,573,508 control chromosomes in the GnomAD database, including 19 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (18 hom.)
• Consequence: MYOM1 NM_003803.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.37

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 18-3164452-TA-T is Benign according to our data. Variant chr18-3164452-TA-T is described in ClinVar as [Likely_benign]. Clinvar id is 227690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOM1	NM_003803.4	c.1340-14del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000356443.9	NP_003794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9	c.1340-14del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_003803.4	ENSP00000348821	P2
MYOM1	ENST00000261606.11	c.1340-14del		splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000261606	A2

Frequencies

GnomAD3 genomes AF: 0.00211 AC: 322 AN: 152250 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00378

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00199 AC: 385 AN: 192998 Hom.: 1 AF XY: 0.00189 AC XY: 196 AN XY: 103836

Gnomad AFR exome AF: 0.000495

Gnomad AMR exome AF: 0.00152

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000415

Gnomad NFE exome AF: 0.00333

Gnomad OTH exome AF: 0.00321

GnomAD4 exome AF: 0.00377 AC: 5359 AN: 1421140 Hom.: 18 Cov.: 31 AF XY: 0.00362 AC XY: 2551 AN XY: 704484

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.00401

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000254

Gnomad4 FIN exome AF: 0.000424

Gnomad4 NFE exome AF: 0.00453

Gnomad4 OTH exome AF: 0.00346

GnomAD4 genome AF: 0.00211 AC: 322 AN: 152368 Hom.: 1 Cov.: 33 AF XY: 0.00184 AC XY: 137 AN XY: 74506

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00378

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00254 Hom.: 0

Bravo AF: 0.00214

ClinVar

Significance: Benign/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

Mar 16, 2015

c.1340-14delT in intron 10 of MYOM1: This variant is not expected to have clinic al significance because it has been identified in 0.4% (118/29586) of European c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs554705715). -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

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: rs554705715; hg19: chr18-3164450;