22-19965653-C-T

Variant summary

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

The NM_000754.4(COMT):c.615+1354C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 151,462 control chromosomes in the GnomAD database, including 31,662 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 0.63 (31622 hom., cov: 34)
  • Exomes 𝑓: 0.76 (40 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40

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]

ARVCF (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMT	NM_000754.4	c.615+1354C>T		intron_variant		ENST00000361682.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMT	ENST00000361682.11	c.615+1354C>T		intron_variant		1	NM_000754.4	P2

Frequencies

GnomAD3 genomes AF: 0.626 AC: 94638 AN: 151202 Hom.: 31626 Cov.: 34

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.724

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.833

Gnomad EAS AF: 0.461

Gnomad SAS AF: 0.550

Gnomad FIN AF: 0.638

Gnomad MID AF: 0.748

Gnomad NFE AF: 0.777

Gnomad OTH AF: 0.654

GnomAD4 exome AF: 0.757 AC: 106 AN: 140 Hom.: 40 Cov.: 0 AF XY: 0.765 AC XY: 78 AN XY: 102

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 1.00

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.800

Gnomad4 OTH exome AF: 0.750

GnomAD4 genome AF: 0.625 AC: 94645 AN: 151322 Hom.: 31622 Cov.: 34 AF XY: 0.618 AC XY: 45685 AN XY: 73964

Gnomad4 AFR AF: 0.412

Gnomad4 AMR AF: 0.543

Gnomad4 ASJ AF: 0.833

Gnomad4 EAS AF: 0.460

Gnomad4 SAS AF: 0.549

Gnomad4 FIN AF: 0.638

Gnomad4 NFE AF: 0.777

Gnomad4 OTH AF: 0.653

Alfa AF: 0.681 Hom.: 11101

Bravo AF: 0.606

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.47
Dann	Benign	0.51

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: rs174696; hg19: chr22-19953176;