rs371754365

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_003803.4(MYOM1):c.1204C>T(p.Arg402Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000179 in 1,612,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R402L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

MYOM1
NM_003803.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 5.61

Publications

4 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27034056).

BP6

Variant 18-3168952-G-A is Benign according to our data. Variant chr18-3168952-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 573920.

BS2

High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOM1	NM_003803.4 link	c.1204C>T	p.Arg402Trp	missense_variant	Exon 9 of 38	ENST00000356443.9	NP_003794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9 link	c.1204C>T	p.Arg402Trp	missense_variant	Exon 9 of 38	1	NM_003803.4	ENSP00000348821.4
MYOM1	ENST00000261606.11 link	c.1204C>T	p.Arg402Trp	missense_variant	Exon 9 of 37	1		ENSP00000261606.7

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

151882

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000147

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000109

AC:

AN:

247210

AF XY:

0.0000746

show subpopulations

Gnomad AFR exome

AF:

0.000261

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000560

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000143

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000183

AC:

268

AN:

1461026

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

726732

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39662

South Asian (SAS)

AF:

0.0000929

AC:

AN:

86150

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000206

AC:

229

AN:

1111556

Other (OTH)

AF:

0.000298

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000132

AC:

AN:

151882

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74156

show subpopulations

African (AFR)

AF:

0.000218

AC:

AN:

41316

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10516

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68010

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000293

Hom.:

Bravo

AF:

0.000155

ESP6500AA

AF:

0.000267

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000993

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Uncertain:1Benign:1

Jun 11, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely benign. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. There is limited evidence regarding variant in this gene. Loss of function is indicated from functional studies in PMID: 21256114. (N) 0107 - This gene is known to be associated with autosomal dominant disease. There is limited evidence for disease-causing variants in this gene. Several reports of putative variants causing hypertrophic cardiomyopathy in families with autosomal dominance inheritance. (PMID: 21256114. PMID: 27600940, PMID: 26656175). There is no disease associated with this gene in OMIM. (N) 0112 - Variants in this gene are known to have reduced penetrance. Limited evidence for disease-causing variants in this gene. There is one report of age-related disease penetrance for a missense variant segregating in a family with HCM. (PMID: 21256114). 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition 0.000133 (37 het, 0 hom). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD:p.(Arg402Gl): 0.00001 (3 het, 0 hom). (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. Major amino acid change, low conservation. (N) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0804 - Variant is present in the population and has previously been described as a variant of uncertain significance (VUS) once in ClinVar. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 402 of the MYOM1 protein (p.Arg402Trp). This variant is present in population databases (rs371754365, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MYOM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 573920). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.061

T;.;.

Eigen

Benign

0.031

Eigen_PC

Benign

0.047

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.27

T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.1

L;.;L

PhyloP100

5.6

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.5

D;.;N

REVEL

Benign

0.21

Sift

Uncertain

0.0040

D;.;D

Sift4G

Uncertain

0.017

D;D;D

Polyphen

0.99

D;.;D

Vest4

0.24

MVP

0.85

MPC

0.48

ClinPred

0.33

GERP RS

5.5

Varity_R

0.11

gMVP

0.61

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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