rs5992500

Variant names:

• chr22-19954424-C-T
• rs5992500
• NM_000754.4:c.-91-6775C>T

Variant summary

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

The NM_000754.4(COMT):​c.-91-6775C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0476 in 152,210 control chromosomes in the GnomAD database, including 496 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 0.048 (496 hom., cov: 32)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0820
• Publications: 5 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4	c.-91-6775C>T		intron_variant	Intron 1 of 5	ENST00000361682.11	NP_000745.1
COMT	NM_001135161.2	c.-92+3372C>T		intron_variant	Intron 1 of 5		NP_001128633.1
COMT	NM_001135162.2	c.-92+2770C>T		intron_variant	Intron 1 of 5		NP_001128634.1
COMT	NM_001362828.2	c.-385-6775C>T		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.-91-6775C>T		intron_variant	Intron 1 of 5	1	NM_000754.4	ENSP00000354511.6

Frequencies

GnomAD3 genomes AF: 0.0476 AC: 7242 AN: 152092 Hom.: 496 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0301

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0791

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00179

Gnomad OTH AF: 0.0330

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

GnomAD4 genome AF: 0.0476 AC: 7250 AN: 152210 Hom.: 496 Cov.: 32 AF XY: 0.0470 AC XY: 3497 AN XY: 74424

African (AFR) AF: 0.147 AC: 6100 AN: 41494

American (AMR) AF: 0.0301 AC: 461 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.0793 AC: 411 AN: 5182

South Asian (SAS) AF: 0.0124 AC: 60 AN: 4820

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10610

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00179 AC: 122 AN: 68022

Other (OTH) AF: 0.0326 AC: 69 AN: 2114

Alfa AF: 0.0273 Hom.: 34

Bravo AF: 0.0561

Asia WGS AF: 0.0500 AC: 176 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.1
DANN	Benign	0.68
PhyloP100		-0.082
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: rs5992500; hg19: chr22-19941947;