Variant 22-19962740-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response,risk factor (no stars).

Frequency

Genomes: 𝑓 0.0086 ( 34 hom., cov: 33)

Exomes 𝑓: 0.0053 ( 201 hom. )

Consequence

COMT
NM_000754.4 missense

Scores

Clinical Significance

drug response; risk factor no assertion criteria provided O:2

Conservation

PhyloP100: 3.56

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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/exons	MANE	UniProt
COMT	NM_000754.4 linkuse as main transcript	c.214G>T	p.Ala72Ser	missense_variant	3/6	ENST00000361682.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMT	ENST00000361682.11 linkuse as main transcript	c.214G>T	p.Ala72Ser	missense_variant	3/6	1	NM_000754.4	P2	P21964-1

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

GnomAD3 exomes

AF:

0.0138

AC:

3468

AN:

250656

Hom.:

AF XY:

0.0119

AC XY:

1622

AN XY:

135740

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 SAS exome

AF:

0.00150

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

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.0375

Gnomad4 ASJ exome

AF:

0.000536

Gnomad4 EAS exome

AF:

0.0706

Gnomad4 SAS exome

AF:

0.00167

Gnomad4 FIN exome

AF:

0.0436

Gnomad4 NFE exome

AF:

0.000456

Gnomad4 OTH exome

AF:

0.00465

GnomAD4 genome

AF:

0.00863

AC:

1314

AN:

152320

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

830

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.0222

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.0491

Gnomad4 SAS

AF:

0.00248

Gnomad4 FIN

AF:

0.0540

Gnomad4 NFE

AF:

0.00140

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00327

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: drug response; risk factor

Submissions summary: Other:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Schizophrenia, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Mar 01, 2005

- -

Tramadol response

Other:1

drug response, no assertion criteria provided

research

Bruce Budowle Laboratory, University of North Texas Health Science Center

Apr 28, 2018

- 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

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

0.78

.;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;.

MutationTaster

Benign

0.81

N;N;N;N;N;N

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

Polyphen

0.74

P;P;P;P;.;P;.

Vest4

0.10

MPC

0.55

ClinPred

0.029

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.33

gMVP

0.74

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over