22-19946255-C-G

Variant names:

• chr22-19946255-C-G
• rs174673
• NM_000754.4:c.-92+4358C>G

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+4358C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.93 in 152,108 control chromosomes in the GnomAD database, including 66,191 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 0.93 (66191 hom., cov: 31)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.94
• Publications: 3 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.979 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4	c.-92+4358C>G		intron_variant	Intron 1 of 5	ENST00000361682.11	NP_000745.1
COMT	NM_001362828.2	c.-386+4358C>G		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+4358C>G		intron_variant	Intron 1 of 5	1	NM_000754.4	ENSP00000354511.6

Frequencies

GnomAD3 genomes AF: 0.930 AC: 141310 AN: 151990 Hom.: 66146 Cov.: 31

Gnomad AFR AF: 0.987

Gnomad AMI AF: 0.988

Gnomad AMR AF: 0.817

Gnomad ASJ AF: 0.960

Gnomad EAS AF: 0.671

Gnomad SAS AF: 0.870

Gnomad FIN AF: 0.878

Gnomad MID AF: 0.943

Gnomad NFE AF: 0.950

Gnomad OTH AF: 0.926

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

GnomAD4 genome AF: 0.930 AC: 141410 AN: 152108 Hom.: 66191 Cov.: 31 AF XY: 0.921 AC XY: 68457 AN XY: 74340

African (AFR) AF: 0.987 AC: 40976 AN: 41524

American (AMR) AF: 0.817 AC: 12456 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.960 AC: 3332 AN: 3472

East Asian (EAS) AF: 0.672 AC: 3450 AN: 5134

South Asian (SAS) AF: 0.870 AC: 4187 AN: 4814

European-Finnish (FIN) AF: 0.878 AC: 9282 AN: 10576

Middle Eastern (MID) AF: 0.952 AC: 278 AN: 292

European-Non Finnish (NFE) AF: 0.950 AC: 64603 AN: 68024

Other (OTH) AF: 0.923 AC: 1945 AN: 2108

Alfa AF: 0.929 Hom.: 7672

Bravo AF: 0.926

Asia WGS AF: 0.775 AC: 2698 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.4
DANN	Benign	0.67
PhyloP100		-1.9
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: rs174673; hg19: chr22-19933778;