rs139422575

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.739G>A(p.Glu247Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00562 in 1,601,050 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0042 ( 5 hom., cov: 30)

Exomes 𝑓: 0.0058 ( 31 hom. )

Consequence

MYOM1
NM_003803.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.35

Publications

11 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 (MetaRNN=0.008267403).

BP6

Variant 18-3188780-C-T is Benign according to our data. Variant chr18-3188780-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 643 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.739G>A	p.Glu247Lys	missense	Exon 4 of 38	NP_003794.3
	MYOM1	NM_019856.2		c.739G>A	p.Glu247Lys	missense	Exon 4 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.739G>A	p.Glu247Lys	missense	Exon 4 of 38	ENSP00000348821.4	P52179-1
MYOM1	ENST00000261606.11	TSL:1	c.739G>A	p.Glu247Lys	missense	Exon 4 of 37	ENSP00000261606.7	P52179-2
MYOM1	ENST00000941943.1		c.739G>A	p.Glu247Lys	missense	Exon 4 of 38	ENSP00000612002.1

Frequencies

GnomAD3 genomes

AF:

0.00423

AC:

643

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00576

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00587

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00635

Gnomad OTH

AF:

0.00288

GnomAD2 exomes

AF:

0.00440

AC:

1061

AN:

241250

AF XY:

0.00450

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00378

Gnomad ASJ exome

AF:

0.00214

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00690

Gnomad NFE exome

AF:

0.00619

Gnomad OTH exome

AF:

0.00566

GnomAD4 exome

AF:

0.00576

AC:

8351

AN:

1448882

Hom.:

Cov.:

AF XY:

0.00560

AC XY:

4025

AN XY:

718942

show subpopulations

African (AFR)

AF:

0.00106

AC:

AN:

33108

American (AMR)

AF:

0.00366

AC:

160

AN:

43736

Ashkenazi Jewish (ASJ)

AF:

0.00192

AC:

AN:

25456

East Asian (EAS)

AF:

0.00

AC:

AN:

39498

South Asian (SAS)

AF:

0.00138

AC:

117

AN:

85088

European-Finnish (FIN)

AF:

0.00667

AC:

354

AN:

53048

Middle Eastern (MID)

AF:

0.00123

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.00667

AC:

7364

AN:

1103500

Other (OTH)

AF:

0.00443

AC:

265

AN:

59756

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

481

962

1443

1924

2405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

272

544

816

1088

1360

<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:

0.00423

AC:

643

AN:

152168

Hom.:

Cov.:

AF XY:

0.00411

AC XY:

306

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.00104

AC:

AN:

41528

American (AMR)

AF:

0.00576

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.000829

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00587

AC:

AN:

10556

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00635

AC:

432

AN:

68026

Other (OTH)

AF:

0.00285

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

118

158

197

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:

0.00546

Hom.:

Bravo

AF:

0.00425

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00180

AC:

ESP6500EA

AF:

0.00557

AC:

ExAC

AF:

0.00386

AC:

467

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Cardiovascular phenotype (1)

Hypertrophic cardiomyopathy (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.066

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0083

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PhyloP100

3.4

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.25

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.037

Polyphen

0.97

Vest4

0.49

MVP

0.83

MPC

0.17

ClinPred

0.011

GERP RS

5.8

Varity_R

0.34

gMVP

0.47

Mutation Taster

=73/27

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