chr18-3134828-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_003803.4(MYOM1):c.2210-4T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,613,960 control chromosomes in the GnomAD database, including 138 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 0.0099 ( 10 hom., cov: 32)

Exomes 𝑓: 0.012 ( 128 hom. )

Consequence

MYOM1
NM_003803.4 splice_region, intron

Scores

Splicing: ADA: 0.00002427

Clinical Significance

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

Conservation

PhyloP100: -0.311

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MYOM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 18-3134828-A-C is Benign according to our data. Variant chr18-3134828-A-C is described in ClinVar as Benign. ClinVar VariationId is 226811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 1504 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOM1	NM_003803.4 link	c.2210-4T>G		splice_region_variant, intron_variant	Intron 15 of 37	ENST00000356443.9	NP_003794.3	P52179-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYOM1	ENST00000356443.9 link	c.2210-4T>G	splice_region_variant, intron_variant	Intron 15 of 37	1	NM_003803.4	ENSP00000348821.4	P52179-1
MYOM1	ENST00000261606.11 link	c.2210-4T>G	splice_region_variant, intron_variant	Intron 15 of 36	1		ENSP00000261606.7	P52179-2
MYOM1	ENST00000577294.1 link	n.*230T>G	downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00988

AC:

1504

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00191

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00635

Gnomad ASJ

AF:

0.00806

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0272

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0146

Gnomad OTH

AF:

0.00622

GnomAD2 exomes

AF:

0.0102

AC:

2534

AN:

249200

AF XY:

0.0101

show subpopulations

Gnomad AFR exome

AF:

0.00174

Gnomad AMR exome

AF:

0.00319

Gnomad ASJ exome

AF:

0.00726

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0287

Gnomad NFE exome

AF:

0.0140

Gnomad OTH exome

AF:

0.0121

GnomAD4 exome

AF:

0.0116

AC:

17005

AN:

1461652

Hom.:

128

Cov.:

AF XY:

0.0114

AC XY:

8260

AN XY:

727118

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

33480

American (AMR)

AF:

0.00358

AC:

160

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00815

AC:

213

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00159

AC:

137

AN:

86256

European-Finnish (FIN)

AF:

0.0268

AC:

1429

AN:

53402

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0130

AC:

14436

AN:

1111818

Other (OTH)

AF:

0.00928

AC:

560

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

801

1602

2403

3204

4005

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

508

1016

1524

2032

2540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00987

AC:

1504

AN:

152308

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

791

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00190

AC:

AN:

41550

American (AMR)

AF:

0.00634

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00806

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00166

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0272

AC:

289

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0146

AC:

990

AN:

68032

Other (OTH)

AF:

0.00616

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

157

235

314

392

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0132

Hom.:

Bravo

AF:

0.00763

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0106

EpiControl

AF:

0.0117

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

2210-4T>G in intron 15 of MYOM1: This variant is not expected to have clinical s ignificance because it is not located within the conserved splice consensus sequ ence. It has been identified in 1.4% (112/8226) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.wa shington.edu/EVS; dbSNP rs143030509). -

MYOM1-related disorder

Benign:1

Dec 11, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Mar 06, 2013

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

6.9

(source)

DANN

Benign

0.36

PhyloP100

-0.31

Mutation Taster

=79/21

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000024

dbscSNV1_RF

Benign

0.0020

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over