rs16944397

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003803.4(MYOM1):c.4358T>C(p.Met1453Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00939 in 1,585,514 control chromosomes in the GnomAD database, including 1,051 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1453L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.047 ( 540 hom., cov: 30)

Exomes 𝑓: 0.0054 ( 511 hom. )

Consequence

MYOM1
NM_003803.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.609

Publications

7 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.7073445E-4).

BP6

Variant 18-3084009-A-G is Benign according to our data. Variant chr18-3084009-A-G is described in ClinVar as Benign. ClinVar VariationId is 226823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOM1	NM_003803.4 link	c.4358T>C	p.Met1453Thr	missense_variant	Exon 32 of 38	ENST00000356443.9	NP_003794.3	P52179-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYOM1	ENST00000356443.9 link	c.4358T>C	p.Met1453Thr	missense_variant	Exon 32 of 38	1	NM_003803.4	ENSP00000348821.4	P52179-1
MYOM1	ENST00000261606.11 link	c.4070T>C	p.Met1357Thr	missense_variant	Exon 31 of 37	1		ENSP00000261606.7	P52179-2
MYOM1	ENST00000581075.1 link	n.*4T>C		non_coding_transcript_exon_variant	Exon 5 of 8	5		ENSP00000462039.1	J3KRK2
MYOM1	ENST00000581075.1 link	n.*4T>C		3_prime_UTR_variant	Exon 5 of 8	5		ENSP00000462039.1	J3KRK2

Frequencies

GnomAD3 genomes

AF:

0.0469

AC:

7131

AN:

152036

Hom.:

540

Cov.:

show subpopulations

Gnomad AFR

AF:

0.161

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0214

Gnomad ASJ

AF:

0.00806

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000764

Gnomad OTH

AF:

0.0316

GnomAD2 exomes

AF:

0.0123

AC:

2534

AN:

206282

AF XY:

0.00927

show subpopulations

Gnomad AFR exome

AF:

0.168

Gnomad AMR exome

AF:

0.00893

Gnomad ASJ exome

AF:

0.00487

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000683

Gnomad OTH exome

AF:

0.00587

GnomAD4 exome

AF:

0.00540

AC:

7742

AN:

1433360

Hom.:

511

Cov.:

AF XY:

0.00471

AC XY:

3345

AN XY:

709914

show subpopulations

African (AFR)

AF:

0.165

AC:

5462

AN:

33134

American (AMR)

AF:

0.0111

AC:

447

AN:

40266

Ashkenazi Jewish (ASJ)

AF:

0.00711

AC:

182

AN:

25598

East Asian (EAS)

AF:

0.00

AC:

AN:

39068

South Asian (SAS)

AF:

0.000293

AC:

AN:

82012

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51806

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.000774

AC:

849

AN:

1096370

Other (OTH)

AF:

0.0121

AC:

717

AN:

59368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

327

655

982

1310

1637

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

352

528

704

880

<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:

0.0470

AC:

7153

AN:

152154

Hom.:

540

Cov.:

AF XY:

0.0447

AC XY:

3321

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.161

AC:

6671

AN:

41450

American (AMR)

AF:

0.0213

AC:

326

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00806

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000830

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000764

AC:

AN:

68024

Other (OTH)

AF:

0.0313

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

299

599

898

1198

1497

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0174

Hom.:

683

Bravo

AF:

0.0546

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.151

AC:

560

ESP6500EA

AF:

0.00134

AC:

ExAC

AF:

0.0130

AC:

1564

Asia WGS

AF:

0.00866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Met1453Thr in exon 32 of MYOM1: This variant is not expected to have clinical si gnificance because it has been identified in 15.1% (560/3712) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs16944397). -

MYOM1-related disorder

Benign:1

Mar 26, 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 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 10, 2012

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

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.019

T;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.21

T;T;T

MetaRNN

Benign

0.00087

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.8

N;.;.

PhyloP100

0.61

PrimateAI

Benign

0.35

PROVEAN

Benign

1.8

N;.;N

REVEL

Benign

0.034

Sift

Benign

1.0

T;.;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.029

MPC

0.16

ClinPred

0.0023

GERP RS

2.3

Varity_R

0.069

gMVP

0.50

Mutation Taster

=92/8

polymorphism (auto)

(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