22-19963240-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000754.4(COMT):c.290-326T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 502,898 control chromosomes in the GnomAD database, including 38,198 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.39 (11566 hom., cov: 32)
  • Exomes 𝑓: 0.38 (26632 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.138

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMT	NM_000754.4	c.290-326T>G		intron_variant		ENST00000361682.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMT	ENST00000361682.11	c.290-326T>G		intron_variant		1	NM_000754.4	P2

Frequencies

GnomAD3 genomes AF: 0.390 AC: 59089 AN: 151694 Hom.: 11563 Cov.: 32

Gnomad AFR AF: 0.417

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.476

Gnomad EAS AF: 0.333

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.402

Gnomad OTH AF: 0.407

GnomAD4 exome AF: 0.384 AC: 134736 AN: 351086 Hom.: 26632 AF XY: 0.384 AC XY: 70104 AN XY: 182706

Gnomad4 AFR exome AF: 0.417

Gnomad4 AMR exome AF: 0.281

Gnomad4 ASJ exome AF: 0.454

Gnomad4 EAS exome AF: 0.316

Gnomad4 SAS exome AF: 0.340

Gnomad4 FIN exome AF: 0.326

Gnomad4 NFE exome AF: 0.404

Gnomad4 OTH exome AF: 0.394

GnomAD4 genome AF: 0.389 AC: 59123 AN: 151812 Hom.: 11566 Cov.: 32 AF XY: 0.384 AC XY: 28480 AN XY: 74186

Gnomad4 AFR AF: 0.417

Gnomad4 AMR AF: 0.334

Gnomad4 ASJ AF: 0.476

Gnomad4 EAS AF: 0.332

Gnomad4 SAS AF: 0.332

Gnomad4 FIN AF: 0.311

Gnomad4 NFE AF: 0.402

Gnomad4 OTH AF: 0.407

Alfa AF: 0.397 Hom.: 2607

Bravo AF: 0.391

Asia WGS AF: 0.331 AC: 1153 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	6.4
Dann	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs740601; hg19: chr22-19950763;