rs165895

chr22-19965536-T-Cchr22-19965536-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.615+1237T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 151,908 control chromosomes in the GnomAD database, including 7,524 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 0.31 (7520 hom., cov: 32)
  • Exomes 𝑓: 0.56 (4 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.533

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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMT	NM_000754.4	c.615+1237T>C		intron_variant		ENST00000361682.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMT	ENST00000361682.11	c.615+1237T>C		intron_variant		1	NM_000754.4	P2

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47159 AN: 151756 Hom.: 7518 Cov.: 32

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.275

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.244

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.349

Gnomad OTH AF: 0.298

GnomAD4 exome AF: 0.559 AC: 19 AN: 34 Hom.: 4 Cov.: 0 AF XY: 0.563 AC XY: 18 AN XY: 32

Gnomad4 SAS exome AF: 0.500

Gnomad4 NFE exome AF: 0.571

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.311 AC: 47162 AN: 151874 Hom.: 7520 Cov.: 32 AF XY: 0.308 AC XY: 22888 AN XY: 74194

Gnomad4 AFR AF: 0.255

Gnomad4 AMR AF: 0.275

Gnomad4 ASJ AF: 0.348

Gnomad4 EAS AF: 0.244

Gnomad4 SAS AF: 0.255

Gnomad4 FIN AF: 0.368

Gnomad4 NFE AF: 0.349

Gnomad4 OTH AF: 0.296

Alfa AF: 0.318 Hom.: 977

Bravo AF: 0.302

Asia WGS AF: 0.258 AC: 897 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	4.3
Dann	Benign	0.29

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: rs165895; hg19: chr22-19953059;