rs174699

Positions:

• chr22-19966935-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.616-1601C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.941 in 985,194 control chromosomes in the GnomAD database, including 436,956 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 0.92 (64811 hom., cov: 31)
  • Exomes 𝑓: 0.94 (372145 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.861

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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.958 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMT	NM_000754.4	c.616-1601C>T		intron_variant		ENST00000361682.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMT	ENST00000361682.11	c.616-1601C>T		intron_variant		1	NM_000754.4	P2

Frequencies

GnomAD3 genomes AF: 0.919 AC: 139757 AN: 152082 Hom.: 64765 Cov.: 31

Gnomad AFR AF: 0.966

Gnomad AMI AF: 0.976

Gnomad AMR AF: 0.820

Gnomad ASJ AF: 0.959

Gnomad EAS AF: 0.597

Gnomad SAS AF: 0.889

Gnomad FIN AF: 0.862

Gnomad MID AF: 0.959

Gnomad NFE AF: 0.945

Gnomad OTH AF: 0.926

GnomAD4 exome AF: 0.945 AC: 786932 AN: 832994 Hom.: 372145 Cov.: 29 AF XY: 0.945 AC XY: 363597 AN XY: 384676

Gnomad4 AFR exome AF: 0.972

Gnomad4 AMR exome AF: 0.749

Gnomad4 ASJ exome AF: 0.956

Gnomad4 EAS exome AF: 0.580

Gnomad4 SAS exome AF: 0.892

Gnomad4 FIN exome AF: 0.873

Gnomad4 NFE exome AF: 0.948

Gnomad4 OTH exome AF: 0.919

GnomAD4 genome AF: 0.919 AC: 139854 AN: 152200 Hom.: 64811 Cov.: 31 AF XY: 0.911 AC XY: 67805 AN XY: 74412

Gnomad4 AFR AF: 0.966

Gnomad4 AMR AF: 0.819

Gnomad4 ASJ AF: 0.959

Gnomad4 EAS AF: 0.597

Gnomad4 SAS AF: 0.888

Gnomad4 FIN AF: 0.862

Gnomad4 NFE AF: 0.945

Gnomad4 OTH AF: 0.924

Alfa AF: 0.933 Hom.: 89745

Bravo AF: 0.914

Asia WGS AF: 0.759 AC: 2642 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.43
DANN	Benign	0.66

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: rs174699; hg19: chr22-19954458;