NM_003803.4:c.4148T>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_003803.4(MYOM1):c.4148T>C(p.Ile1383Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000295 in 1,591,442 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1383N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

MYOM1
NM_003803.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.29

Publications

1 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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2824472).

BS2

High AC in GnomAd4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003803.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOM1	NM_003803.4	MANE Select	c.4148T>C	p.Ile1383Thr	missense	Exon 30 of 38	NP_003794.3
	MYOM1	NM_019856.2		c.3860T>C	p.Ile1287Thr	missense	Exon 29 of 37	NP_062830.1	P52179-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYOM1	ENST00000356443.9	TSL:1 MANE Select	c.4148T>C	p.Ile1383Thr	missense	Exon 30 of 38	ENSP00000348821.4	P52179-1
MYOM1	ENST00000261606.11	TSL:1	c.3860T>C	p.Ile1287Thr	missense	Exon 29 of 37	ENSP00000261606.7	P52179-2
MYOM1	ENST00000941943.1		c.4112T>C	p.Ile1371Thr	missense	Exon 30 of 38	ENSP00000612002.1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000689

AC:

AN:

232378

AF XY:

0.0000712

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000393

Gnomad NFE exome

AF:

0.0000646

Gnomad OTH exome

AF:

0.000179

GnomAD4 exome

AF:

0.0000292

AC:

AN:

1439274

Hom.:

Cov.:

AF XY:

0.0000307

AC XY:

AN XY:

715922

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32744

American (AMR)

AF:

0.00

AC:

AN:

40976

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25462

East Asian (EAS)

AF:

0.00

AC:

AN:

39426

South Asian (SAS)

AF:

0.0000122

AC:

AN:

81804

European-Finnish (FIN)

AF:

0.000310

AC:

AN:

51668

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5676

European-Non Finnish (NFE)

AF:

0.0000218

AC:

AN:

1101946

Other (OTH)

AF:

0.0000168

AC:

AN:

59572

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

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:

0.0000329

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

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:

0.0000764

Hom.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000414

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypertrophic cardiomyopathy (1)

Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.048

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

M_CAP

Benign

0.034

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.70

MutationAssessor

Benign

0.040

PhyloP100

9.3

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.91

REVEL

Uncertain

0.41

Sift

Benign

0.73

Sift4G

Benign

0.47

Polyphen

1.0

Vest4

0.49

MVP

0.84

MPC

0.69

ClinPred

0.21

GERP RS

5.8

Varity_R

0.55

gMVP

0.63

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over