rs165737

Positions:

• chr22-19964978-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+679C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 171,456 control chromosomes in the GnomAD database, including 6,369 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 0.27 (5723 hom., cov: 33)
  • Exomes 𝑓: 0.23 (646 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0970

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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMT	NM_000754.4	c.615+679C>T		intron_variant		ENST00000361682.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMT	ENST00000361682.11	c.615+679C>T		intron_variant		1	NM_000754.4	P2

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40717 AN: 152036 Hom.: 5720 Cov.: 33

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.409

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.264

GnomAD4 exome AF: 0.233 AC: 4504 AN: 19302 Hom.: 646 Cov.: 0 AF XY: 0.233 AC XY: 2347 AN XY: 10090

Gnomad4 AFR exome AF: 0.195

Gnomad4 AMR exome AF: 0.193

Gnomad4 ASJ exome AF: 0.308

Gnomad4 EAS exome AF: 0.0946

Gnomad4 SAS exome AF: 0.172

Gnomad4 FIN exome AF: 0.189

Gnomad4 NFE exome AF: 0.280

Gnomad4 OTH exome AF: 0.247

GnomAD4 genome AF: 0.268 AC: 40724 AN: 152154 Hom.: 5723 Cov.: 33 AF XY: 0.263 AC XY: 19579 AN XY: 74422

Gnomad4 AFR AF: 0.226

Gnomad4 AMR AF: 0.215

Gnomad4 ASJ AF: 0.318

Gnomad4 EAS AF: 0.140

Gnomad4 SAS AF: 0.199

Gnomad4 FIN AF: 0.250

Gnomad4 NFE AF: 0.318

Gnomad4 OTH AF: 0.263

Alfa AF: 0.291 Hom.: 1451

Bravo AF: 0.262

Asia WGS AF: 0.178 AC: 619 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.4
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs165737; hg19: chr22-19952501;