rs4818

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000754.4(COMT):c.408C>G(p.Leu136=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 1,612,472 control chromosomes in the GnomAD database, including 116,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 8487 hom., cov: 33)

Exomes 𝑓: 0.38 ( 107780 hom. )

Consequence

COMT
NM_000754.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:2

Conservation

PhyloP100: 0.271

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 22-19963684-C-G is Benign according to our data. Variant chr22-19963684-C-G is described in ClinVar as [Benign]. Clinvar id is 256786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-19963684-C-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.271 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.391 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.408C>G	p.Leu136=	synonymous_variant	4/6	ENST00000361682.11	NP_000745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COMT	ENST00000361682.11 linkuse as main transcript	c.408C>G	p.Leu136=	synonymous_variant	4/6	1	NM_000754.4	ENSP00000354511	P2	P21964-1

Frequencies

GnomAD3 genomes

AF:

0.324

AC:

49164

AN:

151960

Hom.:

8492

Cov.:

show subpopulations

Gnomad AFR

AF:

0.206

Gnomad AMI

AF:

0.306

Gnomad AMR

AF:

0.304

Gnomad ASJ

AF:

0.471

Gnomad EAS

AF:

0.325

Gnomad SAS

AF:

0.311

Gnomad FIN

AF:

0.301

Gnomad MID

AF:

0.424

Gnomad NFE

AF:

0.395

Gnomad OTH

AF:

0.359

GnomAD3 exomes

AF:

0.338

AC:

84214

AN:

249446

Hom.:

14967

AF XY:

0.346

AC XY:

46860

AN XY:

135238

show subpopulations

Gnomad AFR exome

AF:

0.197

Gnomad AMR exome

AF:

0.213

Gnomad ASJ exome

AF:

0.460

Gnomad EAS exome

AF:

0.323

Gnomad SAS exome

AF:

0.321

Gnomad FIN exome

AF:

0.309

Gnomad NFE exome

AF:

0.395

Gnomad OTH exome

AF:

0.370

GnomAD4 exome

AF:

0.380

AC:

555409

AN:

1460394

Hom.:

107780

Cov.:

AF XY:

0.380

AC XY:

276355

AN XY:

726524

show subpopulations

Gnomad4 AFR exome

AF:

0.197

Gnomad4 AMR exome

AF:

0.222

Gnomad4 ASJ exome

AF:

0.460

Gnomad4 EAS exome

AF:

0.309

Gnomad4 SAS exome

AF:

0.320

Gnomad4 FIN exome

AF:

0.314

Gnomad4 NFE exome

AF:

0.401

Gnomad4 OTH exome

AF:

0.377

GnomAD4 genome

AF:

0.323

AC:

49172

AN:

152078

Hom.:

8487

Cov.:

AF XY:

0.320

AC XY:

23760

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.206

Gnomad4 AMR

AF:

0.304

Gnomad4 ASJ

AF:

0.471

Gnomad4 EAS

AF:

0.324

Gnomad4 SAS

AF:

0.311

Gnomad4 FIN

AF:

0.301

Gnomad4 NFE

AF:

0.395

Gnomad4 OTH

AF:

0.359

Alfa

AF:

0.375

Hom.:

3482

Bravo

AF:

0.317

Asia WGS

AF:

0.311

AC:

1081

AN:

3478

EpiCase

AF:

0.416

EpiControl

AF:

0.409

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:2

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

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 19641441, 9323320, 30218069, 25766270) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

methamphetamine use disorder

Other:1

Uncertain risk allele, no assertion criteria provided

case-control

Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology

Jan 16, 2023

- -

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

BayesDel_noAF

Benign

-0.78

CADD

Benign

3.0

DANN

Benign

0.62

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

3.2

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