rs200480164

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_003803.4(MYOM1):c.3572A>G(p.Asn1191Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000258 in 1,610,858 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. N1191I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0015 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

MYOM1
NM_003803.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.20

Publications

0 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009263873).

BP6

Variant 18-3102477-T-C is Benign according to our data. Variant chr18-3102477-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 416039.

BS2

High AC in GnomAd4 at 225 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOM1	NM_003803.4 link	c.3572A>G	p.Asn1191Ser	missense_variant	Exon 23 of 38	ENST00000356443.9	NP_003794.3	P52179-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9 link	c.3572A>G	p.Asn1191Ser	missense_variant	Exon 23 of 38	1	NM_003803.4	ENSP00000348821.4		P52179-1
MYOM1	ENST00000261606.11 link	c.3284A>G	p.Asn1095Ser	missense_variant	Exon 22 of 37	1		ENSP00000261606.7		P52179-2

Frequencies

GnomAD3 genomes

AF:

0.00147

AC:

224

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00516

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

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

GnomAD2 exomes

AF:

0.000352

AC:

AN:

246950

AF XY:

0.000269

show subpopulations

Gnomad AFR exome

AF:

0.00519

Gnomad AMR exome

AF:

0.000177

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000130

AC:

190

AN:

1458530

Hom.:

Cov.:

AF XY:

0.0000993

AC XY:

AN XY:

725310

show subpopulations

African (AFR)

AF:

0.00492

AC:

164

AN:

33348

American (AMR)

AF:

0.000226

AC:

AN:

44334

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25988

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.00

AC:

AN:

85676

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53330

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1110200

Other (OTH)

AF:

0.000199

AC:

AN:

60250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00148

AC:

225

AN:

152328

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

109

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00517

AC:

215

AN:

41572

American (AMR)

AF:

0.000588

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000701

Hom.:

Bravo

AF:

0.00179

ESP6500AA

AF:

0.00445

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000439

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Jun 16, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Asn1191Ser in exon 23 of MYOM1: This variant is not expected to have clinical significance because it has been identified in 0.5% (51/9776) of African chromos omes including 1 homozygote by the Exome Aggregation Consortium (ExAC, http://ex ac.broadinstitute.org; dbSNP rs200480164). -

MYOM1-related disorder

Benign:1

Oct 28, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hypertrophic cardiomyopathy

Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.062

T;.;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.79

T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.0093

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;.;.

PhyloP100

1.2

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.5

N;.;N

REVEL

Benign

0.075

Sift

Benign

0.24

T;.;T

Sift4G

Benign

0.47

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.14

MVP

0.78

MPC

0.11

ClinPred

0.0086

GERP RS

3.0

Varity_R

0.099

gMVP

0.41

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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