dbSNP rs165599: COMT:c.*522G>A (chr22-19969258-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000754.4(COMT):c.*522G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 154,512 control chromosomes in the GnomAD database, including 26,317 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

Frequency

Genomes: 𝑓 0.56 ( 25871 hom., cov: 33)

Exomes 𝑓: 0.59 ( 446 hom. )

Consequence

COMT
NM_000754.4 3_prime_UTR

Scores

Clinical Significance

drug response no assertion criteria provided O:1

Conservation

PhyloP100: 0.0760

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:

ARVCF (HGNC:728): (ARVCF delta catenin family member) Armadillo Repeat gene deleted in Velo-Cardio-Facial syndrome (ARVCF) is a member of the catenin family. This family plays an important role in the formation of adherens junction complexes, which are thought to facilitate communication between the inside and outside environments of a cell. The ARVCF gene was isolated in the search for the genetic defect responsible for the autosomal dominant Velo-Cardio-Facial syndrome (VCFS), a relatively common human disorder with phenotypic features including cleft palate, conotruncal heart defects and facial dysmorphology. The ARVCF gene encodes a protein containing two motifs, a coiled coil domain in the N-terminus and a 10 armadillo repeat sequence in the midregion. Since these sequences can facilitate protein-protein interactions ARVCF is thought to function in a protein complex. In addition, ARVCF contains a predicted nuclear-targeting sequence suggesting that it may have a function as a nuclear protein. [provided by RefSeq, Jun 2010]

ARVCF links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.689 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4 link	c.*522G>A		3_prime_UTR_variant	Exon 6 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.*522G>A		3_prime_UTR_variant	Exon 6 of 6	1	NM_000754.4	ENSP00000354511.6		P21964-1

Frequencies

GnomAD3 genomes

AF:

0.560

AC:

85081

AN:

151920

Hom.:

25878

Cov.:

show subpopulations

Gnomad AFR

AF:

0.316

Gnomad AMI

AF:

0.796

Gnomad AMR

AF:

0.541

Gnomad ASJ

AF:

0.609

Gnomad EAS

AF:

0.499

Gnomad SAS

AF:

0.568

Gnomad FIN

AF:

0.668

Gnomad MID

AF:

0.655

Gnomad NFE

AF:

0.694

Gnomad OTH

AF:

0.580

GnomAD4 exome

AF:

0.589

AC:

1456

AN:

2474

Hom.:

446

Cov.:

AF XY:

0.576

AC XY:

794

AN XY:

1378

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.452

Gnomad4 ASJ exome

AF:

0.556

Gnomad4 EAS exome

AF:

0.583

Gnomad4 SAS exome

AF:

0.474

Gnomad4 FIN exome

AF:

0.586

Gnomad4 NFE exome

AF:

0.640

Gnomad4 OTH exome

AF:

0.589

GnomAD4 genome

AF:

0.560

AC:

85076

AN:

152038

Hom.:

25871

Cov.:

AF XY:

0.558

AC XY:

41486

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.315

Gnomad4 AMR

AF:

0.540

Gnomad4 ASJ

AF:

0.609

Gnomad4 EAS

AF:

0.499

Gnomad4 SAS

AF:

0.567

Gnomad4 FIN

AF:

0.668

Gnomad4 NFE

AF:

0.694

Gnomad4 OTH

AF:

0.578

Alfa

AF:

0.665

Hom.:

51250

Bravo

AF:

0.538

Asia WGS

AF:

0.531

AC:

1846

AN:

3478

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

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

-0.86

CADD

Benign

1.8

DANN

Benign

0.47

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