22-19962740-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000754.4(COMT):c.214G>T(p.Ala72Ser) 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 1,613,680 control chromosomes in the GnomAD database, including 235 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0086 ( 34 hom., cov: 33)

Exomes 𝑓: 0.0053 ( 201 hom. )

Consequence

COMT
NM_000754.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:2

Conservation

PhyloP100: 3.56

Publications

108 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002458036).

BA1

GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4 link	c.214G>T	p.Ala72Ser	missense_variant	Exon 3 of 6	ENST00000361682.11	NP_000745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COMT	ENST00000361682.11 link	c.214G>T	p.Ala72Ser	missense_variant	Exon 3 of 6	1	NM_000754.4	ENSP00000354511.6

Frequencies

GnomAD3 genomes

AF:

0.00867

AC:

1319

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0224

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.0492

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.0540

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00140

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.0138

AC:

3468

AN:

250656

AF XY:

0.0119

show subpopulations

Gnomad AFR exome

AF:

0.000803

Gnomad AMR exome

AF:

0.0375

Gnomad ASJ exome

AF:

0.000598

Gnomad EAS exome

AF:

0.0469

Gnomad FIN exome

AF:

0.0480

Gnomad NFE exome

AF:

0.00131

Gnomad OTH exome

AF:

0.00963

GnomAD4 exome

AF:

0.00531

AC:

7753

AN:

1461360

Hom.:

201

Cov.:

AF XY:

0.00505

AC XY:

3673

AN XY:

726992

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33480

American (AMR)

AF:

0.0375

AC:

1678

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.000536

AC:

AN:

26132

East Asian (EAS)

AF:

0.0706

AC:

2804

AN:

39698

South Asian (SAS)

AF:

0.00167

AC:

144

AN:

86256

European-Finnish (FIN)

AF:

0.0436

AC:

2310

AN:

52996

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000456

AC:

507

AN:

1111936

Other (OTH)

AF:

0.00465

AC:

281

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

442

884

1325

1767

2209

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<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:

0.00863

AC:

1314

AN:

152320

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

830

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

41566

American (AMR)

AF:

0.0222

AC:

340

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.0491

AC:

254

AN:

5174

South Asian (SAS)

AF:

0.00248

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0540

AC:

574

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00140

AC:

AN:

68032

Other (OTH)

AF:

0.00615

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

119

178

238

297

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:

0.00358

Hom.:

Bravo

AF:

0.00752

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.0116

AC:

1408

Asia WGS

AF:

0.0190

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

22q11.2 deletion syndrome

Uncertain:1

Oct 10, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Schizophrenia, susceptibility to

Other:1

Mar 01, 2005

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

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

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;.;T;T;T;T;.

Eigen

Benign

-0.097

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.0

.;T;.;.;T;T;T

MetaRNN

Benign

0.0025

T;T;T;T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.90

L;.;L;L;.;L;.

PhyloP100

3.6

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.51

N;N;N;.;N;N;N

REVEL

Benign

0.20

Sift

Uncertain

0.022

D;D;D;.;D;D;D

Sift4G

Uncertain

0.015

D;D;D;D;D;D;D

Vest4

0.10

ClinPred

0.029

GERP RS

2.1

PromoterAI

-0.019

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.33

gMVP

0.74

Mutation Taster

=95/5

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