NM_003803.4:c.139A>G

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.139A>G(p.Ser47Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00622 in 1,613,626 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0066 ( 13 hom., cov: 32)

Exomes 𝑓: 0.0062 ( 61 hom. )

Consequence

MYOM1
NM_003803.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.14

Publications

10 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:

ENSG00000265399 (HGNC:):

ENSG00000265399 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=0.0047293007).

BP6

Variant 18-3215085-T-C is Benign according to our data. Variant chr18-3215085-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 1007 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOM1	NM_003803.4 link	c.139A>G	p.Ser47Gly	missense_variant	Exon 2 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.139A>G	p.Ser47Gly	missense_variant	Exon 2 of 38	1	NM_003803.4	ENSP00000348821.4	P52179-1
MYOM1	ENST00000261606.11 link	c.139A>G	p.Ser47Gly	missense_variant	Exon 2 of 37	1		ENSP00000261606.7	P52179-2
ENSG00000265399	ENST00000580139.1 link	n.198-1907T>C		intron_variant	Intron 2 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.00662

AC:

1008

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000868

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.0173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0420

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00628

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00663

AC:

1639

AN:

247328

AF XY:

0.00641

show subpopulations

Gnomad AFR exome

AF:

0.000722

Gnomad AMR exome

AF:

0.00128

Gnomad ASJ exome

AF:

0.0158

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0372

Gnomad NFE exome

AF:

0.00527

Gnomad OTH exome

AF:

0.00734

GnomAD4 exome

AF:

0.00618

AC:

9028

AN:

1461326

Hom.:

Cov.:

AF XY:

0.00611

AC XY:

4439

AN XY:

726988

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33476

American (AMR)

AF:

0.00150

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0151

AC:

395

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0388

AC:

2062

AN:

53156

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00543

AC:

6034

AN:

1111816

Other (OTH)

AF:

0.00731

AC:

441

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

551

1102

1654

2205

2756

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

224

448

672

896

1120

<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:

0.00661

AC:

1007

AN:

152300

Hom.:

Cov.:

AF XY:

0.00791

AC XY:

589

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.000865

AC:

AN:

41596

American (AMR)

AF:

0.00183

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0173

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0420

AC:

446

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00626

AC:

426

AN:

68016

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

143

191

239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00526

Hom.:

Bravo

AF:

0.00324

ESP6500AA

AF:

0.000983

AC:

ESP6500EA

AF:

0.00251

AC:

ExAC

AF:

0.00529

AC:

640

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00513

EpiControl

AF:

0.00379

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYOM1: BP4, BS2 -

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

Ser47Gly in exon 2 of MYOM1: This variant is not expected to have clinical signi ficance because it has been identified in 4.3% (8/186) of Finnish chromosomes fr om a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov/p rojects/SNP; dbSNP rs202145133). -

Hypertrophic cardiomyopathy

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Oct 24, 2013

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

0.25

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.039

T;.

Eigen

Benign

-0.018

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.75

T;T

MetaRNN

Benign

0.0047

T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

2.0

M;M

PhyloP100

1.1

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.92

N;N

REVEL

Benign

0.052

Sift

Uncertain

0.010

D;D

Sift4G

Uncertain

0.045

D;D

Polyphen

0.20

B;B

Vest4

0.36

MVP

0.78

MPC

0.13

ClinPred

0.0097

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.54

Mutation Taster

=95/5

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

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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