rs77613865

Positions:

chr18-3149142-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The ENST00000356443.9(MYOM1):c.1900+3A>C variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.00206 in 1,613,738 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0054 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 44 hom. )

Consequence

MYOM1
ENST00000356443.9 splice_donor_region, intron

Scores

Splicing: ADA: 0.9734

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:4

Conservation

PhyloP100: 5.56

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 -16 ACMG points.

BP6

Variant 18-3149142-T-G is Benign according to our data. Variant chr18-3149142-T-G is described in ClinVar as [Benign]. Clinvar id is 180694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0054 (822/152320) while in subpopulation AFR AF= 0.0171 (709/41562). AF 95% confidence interval is 0.016. There are 7 homozygotes in gnomad4. There are 381 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOM1	NM_003803.4 linkuse as main transcript	c.1900+3A>C		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.1900+3A>C		splice_donor_region_variant, intron_variant		1	NM_003803.4	ENSP00000348821	P2	P52179-1
MYOM1	ENST00000261606.11 linkuse as main transcript	c.1900+3A>C		splice_donor_region_variant, intron_variant		1		ENSP00000261606	A2	P52179-2

Frequencies

GnomAD3 genomes

AF:

0.00534

AC:

813

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0143

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00348

AC:

868

AN:

249234

Hom.:

AF XY:

0.00388

AC XY:

525

AN XY:

135198

show subpopulations

Gnomad AFR exome

AF:

0.0164

Gnomad AMR exome

AF:

0.000637

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0184

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000133

Gnomad OTH exome

AF:

0.00248

GnomAD4 exome

AF:

0.00171

AC:

2500

AN:

1461418

Hom.:

Cov.:

AF XY:

0.00214

AC XY:

1556

AN XY:

726972

show subpopulations

Gnomad4 AFR exome

AF:

0.0181

Gnomad4 AMR exome

AF:

0.000760

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0180

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.0000953

Gnomad4 OTH exome

AF:

0.00305

GnomAD4 genome

AF:

0.00540

AC:

822

AN:

152320

Hom.:

Cov.:

AF XY:

0.00511

AC XY:

381

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0171

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00291

Hom.:

Bravo

AF:

0.00524

Asia WGS

AF:

0.0180

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:1Benign:1

Likely pathogenic, no assertion criteria provided	clinical testing	Strand Center for Genomics and Personalized Medicine, Strand Life Sciences Pvt Ltd	Jun 12, 2014	This MYOM1 splice site variant c.1900+3A>C was found homozygously in a 3 year old female child suffering from hypertrophic cardiomyopathy. The change is likely to result in a shorter protein of 644 amino acids. This truncated protein lacks the the fibronectin type III and Ig-like C2-type domains, region which mainly play a role in dimerization, implying an altered dimerization of the protein. A missense variant that affects the dimerization of domain 13 has been reported to be involved in the pathogenesis of Hypertrophic cardiomyopathy (HCM) (PMID: 21256114). -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

1900+3A>C in intron 13 of MYOM1: This variant is not expected to have clinical s ignificance because it has been identified in 1.7% (73/4268) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs77613865). -

MYOM1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 27, 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). -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2013

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Pathogenic

0.73

SpliceAI score (max)

0.17

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

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