18-3100431-G-A

Position:

chr18-3100431-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003803.4(MYOM1):c.3576-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.43 in 1,606,494 control chromosomes in the GnomAD database, including 152,167 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 11665 hom., cov: 31)

Exomes 𝑓: 0.44 ( 140502 hom. )

Consequence

MYOM1
NM_003803.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00001161

Clinical Significance

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

Conservation

PhyloP100: -0.0800

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 18-3100431-G-A is Benign according to our data. Variant chr18-3100431-G-A is described in ClinVar as [Benign]. Clinvar id is 226819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM1	NM_003803.4 linkuse as main transcript	c.3576-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000356443.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM1	ENST00000356443.9 linkuse as main transcript	c.3576-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_003803.4	P2	P52179-1
MYOM1	ENST00000261606.11 linkuse as main transcript	c.3288-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		A2	P52179-2

Frequencies

GnomAD3 genomes

AF:

0.373

AC:

56617

AN:

151778

Hom.:

11659

Cov.:

show subpopulations

Gnomad AFR

AF:

0.193

Gnomad AMI

AF:

0.434

Gnomad AMR

AF:

0.512

Gnomad ASJ

AF:

0.456

Gnomad EAS

AF:

0.354

Gnomad SAS

AF:

0.359

Gnomad FIN

AF:

0.355

Gnomad MID

AF:

0.465

Gnomad NFE

AF:

0.449

Gnomad OTH

AF:

0.445

GnomAD3 exomes

AF:

0.427

AC:

104347

AN:

244570

Hom.:

23079

AF XY:

0.426

AC XY:

56459

AN XY:

132552

show subpopulations

Gnomad AFR exome

AF:

0.188

Gnomad AMR exome

AF:

0.578

Gnomad ASJ exome

AF:

0.463

Gnomad EAS exome

AF:

0.360

Gnomad SAS exome

AF:

0.376

Gnomad FIN exome

AF:

0.355

Gnomad NFE exome

AF:

0.446

Gnomad OTH exome

AF:

0.454

GnomAD4 exome

AF:

0.436

AC:

633726

AN:

1454598

Hom.:

140502

Cov.:

AF XY:

0.435

AC XY:

314661

AN XY:

723666

show subpopulations

Gnomad4 AFR exome

AF:

0.183

Gnomad4 AMR exome

AF:

0.570

Gnomad4 ASJ exome

AF:

0.454

Gnomad4 EAS exome

AF:

0.345

Gnomad4 SAS exome

AF:

0.377

Gnomad4 FIN exome

AF:

0.357

Gnomad4 NFE exome

AF:

0.449

Gnomad4 OTH exome

AF:

0.429

GnomAD4 genome

AF:

0.373

AC:

56644

AN:

151896

Hom.:

11665

Cov.:

AF XY:

0.370

AC XY:

27477

AN XY:

74204

show subpopulations

Gnomad4 AFR

AF:

0.193

Gnomad4 AMR

AF:

0.512

Gnomad4 ASJ

AF:

0.456

Gnomad4 EAS

AF:

0.355

Gnomad4 SAS

AF:

0.359

Gnomad4 FIN

AF:

0.355

Gnomad4 NFE

AF:

0.449

Gnomad4 OTH

AF:

0.442

Alfa

AF:

0.426

Hom.:

7979

Bravo

AF:

0.379

Asia WGS

AF:

0.356

AC:

1240

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

3576-5C>T in intron 23 of MYOM1: This variant is not expected to have clinical s ignificance because it has been identified in 44.7% (3679/8230) of European Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs7232329). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 13, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hypertrophic cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2012

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

-0.88

CADD

Benign

3.4

DANN

Benign

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000012

dbscSNV1_RF

Benign

0.0

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

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