rs4680

Positions:

chr22-19963748-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000754.4(COMT):c.472G>A(p.Val158Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 1,610,688 control chromosomes in the GnomAD database, including 197,380 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.44 ( 15489 hom., cov: 33)

Exomes 𝑓: 0.50 ( 181891 hom. )

Consequence

COMT
NM_000754.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 0.146

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:

MIR4761 (HGNC:41591): (microRNA 4761) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR4761 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.567385E-5).

BP6

Variant 22-19963748-G-A is Benign according to our data. Variant chr22-19963748-G-A is described in ClinVar as [Benign]. Clinvar id is 17591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-19963748-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COMT	NM_000754.4 linkuse as main transcript	c.472G>A	p.Val158Met	missense_variant	4/6	ENST00000361682.11	NP_000745.1
MIR4761	NR_039918.1 linkuse as main transcript			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COMT	ENST00000361682.11 linkuse as main transcript	c.472G>A	p.Val158Met	missense_variant	4/6	1	NM_000754.4	ENSP00000354511	P2	P21964-1
MIR4761	ENST00000585066.1 linkuse as main transcript			upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.440

AC:

66834

AN:

151946

Hom.:

15493

Cov.:

show subpopulations

Gnomad AFR

AF:

0.310

Gnomad AMI

AF:

0.664

Gnomad AMR

AF:

0.405

Gnomad ASJ

AF:

0.453

Gnomad EAS

AF:

0.274

Gnomad SAS

AF:

0.446

Gnomad FIN

AF:

0.553

Gnomad MID

AF:

0.465

Gnomad NFE

AF:

0.518

Gnomad OTH

AF:

0.420

GnomAD3 exomes

AF:

0.461

AC:

114049

AN:

247346

Hom.:

27151

AF XY:

0.465

AC XY:

62409

AN XY:

134140

show subpopulations

Gnomad AFR exome

AF:

0.311

Gnomad AMR exome

AF:

0.405

Gnomad ASJ exome

AF:

0.461

Gnomad EAS exome

AF:

0.272

Gnomad SAS exome

AF:

0.440

Gnomad FIN exome

AF:

0.553

Gnomad NFE exome

AF:

0.520

Gnomad OTH exome

AF:

0.474

GnomAD4 exome

AF:

0.496

AC:

723171

AN:

1458624

Hom.:

181891

Cov.:

AF XY:

0.495

AC XY:

359427

AN XY:

725604

show subpopulations

Gnomad4 AFR exome

AF:

0.301

Gnomad4 AMR exome

AF:

0.408

Gnomad4 ASJ exome

AF:

0.460

Gnomad4 EAS exome

AF:

0.286

Gnomad4 SAS exome

AF:

0.448

Gnomad4 FIN exome

AF:

0.550

Gnomad4 NFE exome

AF:

0.516

Gnomad4 OTH exome

AF:

0.465

GnomAD4 genome

AF:

0.440

AC:

66839

AN:

152064

Hom.:

15489

Cov.:

AF XY:

0.440

AC XY:

32667

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.310

Gnomad4 AMR

AF:

0.404

Gnomad4 ASJ

AF:

0.453

Gnomad4 EAS

AF:

0.274

Gnomad4 SAS

AF:

0.445

Gnomad4 FIN

AF:

0.553

Gnomad4 NFE

AF:

0.518

Gnomad4 OTH

AF:

0.418

Alfa

AF:

0.487

Hom.:

36118

Bravo

AF:

0.420

TwinsUK

AF:

0.502

AC:

1860

ALSPAC

AF:

0.512

AC:

1974

ESP6500AA

AF:

0.315

AC:

1387

ESP6500EA

AF:

0.522

AC:

4485

ExAC

AF:

0.462

AC:

56093

Asia WGS

AF:

0.344

AC:

1197

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Schizophrenia

Benign:1

Benign, criteria provided, single submitter

case-control

Center for Forensic Mental Health, Chiba University

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

CATECHOL-O-METHYLTRANSFERASE POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jan 01, 2011

- -

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

-0.44

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

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

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.64

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

MetaRNN

Benign

0.000066

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

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.0

M;.;M;M;.;M;.

MutationTaster

Benign

1.0

P;P;P;P;P;P

PrimateAI

Benign

0.32

PROVEAN

Benign

0.66

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

REVEL

Benign

0.25

Sift

Benign

0.22

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

Sift4G

Uncertain

0.029

D;D;D;D;D;D;T

Polyphen

0.016

B;P;B;B;.;B;.

Vest4

0.073

MPC

0.36

ClinPred

0.0047

GERP RS

-0.75

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.46

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