chr18-3134646-T-A

Position:

chr18-3134646-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

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:1B:4

Conservation

PhyloP100: 4.43

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	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 linkuse as main transcript	c.2384+4A>T		splice_donor_region_variant, intron_variant		1	NM_003803.4	ENSP00000348821	P2	P52179-1
MYOM1	ENST00000261606.11 linkuse as main transcript	c.2384+4A>T		splice_donor_region_variant, intron_variant		1		ENSP00000261606	A2	P52179-2

Frequencies

GnomAD3 genomes

AF:

0.00264

AC:

401

AN:

152164

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000531

AC XY:

AN XY:

133798

show subpopulations

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.:

Cov.:

AF XY:

0.000234

AC XY:

169

AN XY:

723040

show subpopulations

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.:

Cov.:

AF XY:

0.00267

AC XY:

199

AN XY:

74442

show subpopulations

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.:

Bravo

AF:

0.00296

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign: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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over