rs174675

Variant names:

• chr22-19946528-T-C
• rs174675
• NM_000754.4:c.-92+4631T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000754.4(COMT):​c.-92+4631T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 152,030 control chromosomes in the GnomAD database, including 34,876 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 0.67 (34876 hom., cov: 32)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.81
• Publications: 32 publications found

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]

COMT Gene-Disease associations (from GenCC):

• paroxysmal dyskinesia

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.07).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.712 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4	c.-92+4631T>C		intron_variant	Intron 1 of 5	ENST00000361682.11	NP_000745.1
COMT	NM_001362828.2	c.-386+4631T>C		intron_variant	Intron 1 of 5		NP_001349757.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COMT	ENST00000361682.11	c.-92+4631T>C		intron_variant	Intron 1 of 5	1	NM_000754.4	ENSP00000354511.6

Frequencies

GnomAD3 genomes AF: 0.675 AC: 102563 AN: 151914 Hom.: 34865 Cov.: 32

Gnomad AFR AF: 0.651

Gnomad AMI AF: 0.675

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.716

Gnomad EAS AF: 0.565

Gnomad SAS AF: 0.627

Gnomad FIN AF: 0.708

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.717

Gnomad OTH AF: 0.653

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.675 AC: 102620 AN: 152030 Hom.: 34876 Cov.: 32 AF XY: 0.670 AC XY: 49812 AN XY: 74294

African (AFR) AF: 0.651 AC: 26962 AN: 41448

American (AMR) AF: 0.575 AC: 8787 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.716 AC: 2484 AN: 3468

East Asian (EAS) AF: 0.565 AC: 2910 AN: 5150

South Asian (SAS) AF: 0.627 AC: 3022 AN: 4820

European-Finnish (FIN) AF: 0.708 AC: 7483 AN: 10564

Middle Eastern (MID) AF: 0.769 AC: 226 AN: 294

European-Non Finnish (NFE) AF: 0.717 AC: 48759 AN: 67994

Other (OTH) AF: 0.652 AC: 1374 AN: 2108

Alfa AF: 0.699 Hom.: 55137

Bravo AF: 0.660

Asia WGS AF: 0.606 AC: 2109 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.25
DANN	Benign	0.41
PhyloP100		-3.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs174675; hg19: chr22-19934051;