18-3134646-T-A

Position:

• chr18-3134646-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_003803.4(MYOM1):​c.2384+4A>T variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.000493 in 1,607,898 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: MYOM1 NM_003803.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.7316
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:4
• Conservation: PhyloP100: 4.43

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 18-3134646-T-A is Benign according to our data. Variant chr18-3134646-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 226812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOM1	NM_003803.4	c.2384+4A>T		splice_donor_region_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.2384+4A>T		splice_donor_region_variant, intron_variant		1	NM_003803.4	ENSP00000348821	P2
MYOM1	ENST00000261606.11	c.2384+4A>T		splice_donor_region_variant, intron_variant		1		ENSP00000261606	A2

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 401 AN: 152164 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

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: 0.000478

GnomAD3 exomes AF: 0.000701 AC: 173 AN: 246684 Hom.: 1 AF XY: 0.000531 AC XY: 71 AN XY: 133798

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000269 AC: 391 AN: 1455616 Hom.: 1 Cov.: 31 AF XY: 0.000234 AC XY: 169 AN XY: 723040

Gnomad4 AFR exome AF: 0.0101

Gnomad4 AMR exome AF: 0.000269

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000350

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000632

Gnomad4 OTH exome AF: 0.000516

GnomAD4 genome AF: 0.00264 AC: 402 AN: 152282 Hom.: 3 Cov.: 32 AF XY: 0.00267 AC XY: 199 AN XY: 74442

Gnomad4 AFR AF: 0.00941

Gnomad4 AMR AF: 0.000654

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: 0.000473

Alfa AF: 0.000649 Hom.: 0

Bravo AF: 0.00296

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 10, 2015	c.2384+4A>T in intron 16 of MYOM1: This variant is not expected to have clinical significance because it has been identified in 1.0% (98/9464) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs73373171). -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 07, 2013	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Splice site variant (c.2384+4 A>T) in the MYOM1 gene Based on the information reviewed below, we categorize it as a VUS, probably benign due to its frequency in African Americans in population datasets. (Our patient is African American.) The c.2384+4 A>T variant is located in intron 16 of the MYOM1 gene, four nucleotides after exon 16. This variant was previously reported in the SNPDatabase as rs73373171. Based on data from the NHLBI Exome Sequencing Project (ESP), the T-allele has an overall frequency of approximately 0.23% (23/9,826), having been observed in 0.73% (23/3,154) of African American alleles, and in 0.0% (0/6,672) of European American alleles. Based on data from the 1000 Genomes Project, the A-allele has an overall frequency of approximately 0.23% (5/2,188). The highest observed frequency was 3 of 194 (1.55%) Luhya West African chromosomes studied. Based on nucleotide sequence alignment in 37 available vertebrate species, this nucleotide position is conserved in 35 of them. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native donor splice site; however, direct evidence of the effect on splicing is unavailable. -

MYOM1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 06, 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). -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2013

Does not segregate with disease in family study (genes with incomplete penetrance);Subpopulation frequency in support of benign classification -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.73
dbscSNV1_RF	Benign	0.71
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.46		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs73373171; hg19: chr18-3134644;