rs3788319

chr22-19942028-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000754.4(COMT):c.-92+131A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 383,990 control chromosomes in the GnomAD database, including 50,195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.52 (20442 hom., cov: 30)
  • Exomes 𝑓: 0.50 (29753 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.47

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 22-19942028-A-G is Benign according to our data. Variant chr22-19942028-A-G is described in ClinVar as [Benign]. Clinvar id is 678640.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.569 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMT	NM_000754.4	c.-92+131A>G		intron_variant		ENST00000361682.11
COMT	NM_001362828.2	c.-386+131A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMT	ENST00000361682.11	c.-92+131A>G		intron_variant		1	NM_000754.4	P2

Frequencies

GnomAD3 genomes AF: 0.515 AC: 77847 AN: 151122 Hom.: 20416 Cov.: 30

Gnomad AFR AF: 0.575

Gnomad AMI AF: 0.481

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.673

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.508

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.548

Gnomad NFE AF: 0.513

Gnomad OTH AF: 0.554

GnomAD4 exome AF: 0.503 AC: 117020 AN: 232756 Hom.: 29753 Cov.: 4 AF XY: 0.506 AC XY: 61008 AN XY: 120590

Gnomad4 AFR exome AF: 0.568

Gnomad4 AMR exome AF: 0.430

Gnomad4 ASJ exome AF: 0.664

Gnomad4 EAS exome AF: 0.381

Gnomad4 SAS exome AF: 0.510

Gnomad4 FIN exome AF: 0.387

Gnomad4 NFE exome AF: 0.520

Gnomad4 OTH exome AF: 0.519

GnomAD4 genome AF: 0.515 AC: 77914 AN: 151234 Hom.: 20442 Cov.: 30 AF XY: 0.509 AC XY: 37583 AN XY: 73856

Gnomad4 AFR AF: 0.575

Gnomad4 AMR AF: 0.473

Gnomad4 ASJ AF: 0.673

Gnomad4 EAS AF: 0.386

Gnomad4 SAS AF: 0.508

Gnomad4 FIN AF: 0.364

Gnomad4 NFE AF: 0.513

Gnomad4 OTH AF: 0.552

Alfa AF: 0.509 Hom.: 2827

Bravo AF: 0.522

Asia WGS AF: 0.443 AC: 1542 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 15, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	1.2
Dann	Benign	0.55

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

Other links and lift over

dbSNP: rs3788319; hg19: chr22-19929551; COSMIC: COSV57634808; COSMIC: COSV57634808;