dbSNP rs2239393: COMT:c.289+90A>G (chr22-19962905-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_000754.4(COMT):c.289+90A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 1,468,990 control chromosomes in the GnomAD database, including 114,894 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 11464 hom., cov: 33)

Exomes 𝑓: 0.39 ( 103430 hom. )

Consequence

COMT
NM_000754.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: -1.77

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 22-19962905-A-G is Benign according to our data. Variant chr22-19962905-A-G is described in ClinVar as [Benign]. Clinvar id is 829771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4 link	c.289+90A>G		intron_variant	Intron 3 of 5	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.289+90A>G		intron_variant	Intron 3 of 5	1	NM_000754.4	ENSP00000354511.6		P21964-1

Frequencies

GnomAD3 genomes

AF:

0.388

AC:

58883

AN:

151854

Hom.:

11461

Cov.:

show subpopulations

Gnomad AFR

AF:

0.414

Gnomad AMI

AF:

0.309

Gnomad AMR

AF:

0.334

Gnomad ASJ

AF:

0.475

Gnomad EAS

AF:

0.324

Gnomad SAS

AF:

0.329

Gnomad FIN

AF:

0.310

Gnomad MID

AF:

0.427

Gnomad NFE

AF:

0.401

Gnomad OTH

AF:

0.405

GnomAD4 exome

AF:

0.394

AC:

519021

AN:

1317018

Hom.:

103430

Cov.:

AF XY:

0.394

AC XY:

253892

AN XY:

644606

show subpopulations

Gnomad4 AFR exome

AF:

0.407

Gnomad4 AMR exome

AF:

0.252

Gnomad4 ASJ exome

AF:

0.467

Gnomad4 EAS exome

AF:

0.299

Gnomad4 SAS exome

AF:

0.339

Gnomad4 FIN exome

AF:

0.327

Gnomad4 NFE exome

AF:

0.407

Gnomad4 OTH exome

AF:

0.400

GnomAD4 genome

AF:

0.388

AC:

58919

AN:

151972

Hom.:

11464

Cov.:

AF XY:

0.382

AC XY:

28381

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.414

Gnomad4 AMR

AF:

0.333

Gnomad4 ASJ

AF:

0.475

Gnomad4 EAS

AF:

0.323

Gnomad4 SAS

AF:

0.330

Gnomad4 FIN

AF:

0.310

Gnomad4 NFE

AF:

0.401

Gnomad4 OTH

AF:

0.405

Alfa

AF:

0.403

Hom.:

19270

Bravo

AF:

0.390

Asia WGS

AF:

0.329

AC:

1147

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

-0.90

CADD

Benign

0.19

DANN

Benign

0.37

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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