rs769224

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000754.4(COMT):c.597G>A(p.Pro199Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0263 in 1,613,964 control chromosomes in the GnomAD database, including 799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.043 ( 219 hom., cov: 33)

Exomes 𝑓: 0.025 ( 580 hom. )

Consequence

COMT
NM_000754.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: -1.92

Publications

26 publications found

Variant links:

Genes affected

COMT (HGNC:2228): (catechol-O-methyltransferase) Catechol-O-methyltransferase catalyzes the transfer of a methyl group from S-adenosylmethionine to catecholamines, including the neurotransmitters dopamine, epinephrine, and norepinephrine. This O-methylation results in one of the major degradative pathways of the catecholamine transmitters. In addition to its role in the metabolism of endogenous substances, COMT is important in the metabolism of catechol drugs used in the treatment of hypertension, asthma, and Parkinson disease. COMT is found in two forms in tissues, a soluble form (S-COMT) and a membrane-bound form (MB-COMT). The differences between S-COMT and MB-COMT reside within the N-termini. Several transcript variants are formed through the use of alternative translation initiation sites and promoters. [provided by RefSeq, Sep 2008]

COMT Gene-Disease associations (from GenCC):

paroxysmal dyskinesia
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

COMT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.121).

BP6

Variant 22-19964281-G-A is Benign according to our data. Variant chr22-19964281-G-A is described in ClinVar as Benign. ClinVar VariationId is 828956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.92 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0909 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4 link	c.597G>A	p.Pro199Pro	synonymous_variant	Exon 5 of 6	ENST00000361682.11	NP_000745.1	P21964-1A0A140VJG8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COMT	ENST00000361682.11 link	c.597G>A	p.Pro199Pro	synonymous_variant	Exon 5 of 6	1	NM_000754.4	ENSP00000354511.6		P21964-1

Frequencies

GnomAD3 genomes

AF:

0.0432

AC:

6579

AN:

152172

Hom.:

219

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0934

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0288

Gnomad ASJ

AF:

0.0208

Gnomad EAS

AF:

0.0644

Gnomad SAS

AF:

0.0205

Gnomad FIN

AF:

0.0203

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0218

Gnomad OTH

AF:

0.0297

GnomAD2 exomes

AF:

0.0302

AC:

7592

AN:

251326

AF XY:

0.0282

show subpopulations

Gnomad AFR exome

AF:

0.0924

Gnomad AMR exome

AF:

0.0267

Gnomad ASJ exome

AF:

0.0205

Gnomad EAS exome

AF:

0.0696

Gnomad FIN exome

AF:

0.0198

Gnomad NFE exome

AF:

0.0217

Gnomad OTH exome

AF:

0.0231

GnomAD4 exome

AF:

0.0245

AC:

35875

AN:

1461674

Hom.:

580

Cov.:

AF XY:

0.0242

AC XY:

17580

AN XY:

727154

show subpopulations

African (AFR)

AF:

0.0934

AC:

3127

AN:

33480

American (AMR)

AF:

0.0258

AC:

1152

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0215

AC:

561

AN:

26136

East Asian (EAS)

AF:

0.0533

AC:

2116

AN:

39700

South Asian (SAS)

AF:

0.0219

AC:

1890

AN:

86258

European-Finnish (FIN)

AF:

0.0172

AC:

913

AN:

53214

Middle Eastern (MID)

AF:

0.0260

AC:

150

AN:

5768

European-Non Finnish (NFE)

AF:

0.0219

AC:

24302

AN:

1112004

Other (OTH)

AF:

0.0276

AC:

1664

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

2337

4674

7012

9349

11686

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

998

1996

2994

3992

4990

<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:

0.0433

AC:

6589

AN:

152290

Hom.:

219

Cov.:

AF XY:

0.0431

AC XY:

3207

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0933

AC:

3878

AN:

41548

American (AMR)

AF:

0.0289

AC:

442

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0208

AC:

AN:

3468

East Asian (EAS)

AF:

0.0645

AC:

334

AN:

5178

South Asian (SAS)

AF:

0.0205

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0203

AC:

216

AN:

10624

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0218

AC:

1481

AN:

68018

Other (OTH)

AF:

0.0294

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

311

623

934

1246

1557

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<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:

0.0284

Hom.:

371

Bravo

AF:

0.0462

Asia WGS

AF:

0.0380

AC:

134

AN:

3478

EpiCase

AF:

0.0215

EpiControl

AF:

0.0223

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 05, 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

- -

Tramadol response

Other:1

Apr 28, 2018

Bruce Budowle Laboratory, University of North Texas Health Science Center

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:research

- T:M1 = postmortem ratio or tramadol to O-desmethyltramadol; t-MP = model-based clustered metabolizer phenotype inferred from T:M1

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

2.3

(source)

DANN

Benign

0.78

PhyloP100

-1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(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