22-19943884-T-C

Variant names:

• chr22-19943884-T-C
• rs933271
• NM_000754.4:c.-92+1987T>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+1987T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 147,418 control chromosomes in the GnomAD database, including 9,242 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 0.35 (9242 hom., cov: 31)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.442
• Publications: 53 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000754.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	NM_000754.4	MANE Select	c.-92+1987T>C		intron	N/A	NP_000745.1
	COMT	NM_001362828.2		c.-386+1987T>C		intron	N/A	NP_001349757.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	ENST00000361682.11	TSL:1 MANE Select	c.-92+1987T>C		intron	N/A	ENSP00000354511.6
	COMT	ENST00000678769.1		c.-92+1987T>C		intron	N/A	ENSP00000503289.1
	COMT	ENST00000428707.2	TSL:3	c.-92+1987T>C		intron	N/A	ENSP00000387695.2

Frequencies

GnomAD3 genomes AF: 0.352 AC: 51873 AN: 147302 Hom.: 9226 Cov.: 31

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.444

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.394

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.265

Gnomad NFE AF: 0.292

Gnomad OTH AF: 0.376

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

GnomAD4 genome AF: 0.352 AC: 51942 AN: 147418 Hom.: 9242 Cov.: 31 AF XY: 0.356 AC XY: 25671 AN XY: 72032

African (AFR) AF: 0.416 AC: 16917 AN: 40646

American (AMR) AF: 0.445 AC: 6559 AN: 14746

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 983 AN: 3224

East Asian (EAS) AF: 0.455 AC: 2240 AN: 4928

South Asian (SAS) AF: 0.394 AC: 1801 AN: 4570

European-Finnish (FIN) AF: 0.298 AC: 3076 AN: 10324

Middle Eastern (MID) AF: 0.245 AC: 67 AN: 274

European-Non Finnish (NFE) AF: 0.292 AC: 19238 AN: 65778

Other (OTH) AF: 0.377 AC: 764 AN: 2028

Alfa AF: 0.313 Hom.: 21550

Bravo AF: 0.358

Asia WGS AF: 0.394 AC: 1371 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.4
DANN	Benign	0.62
PhyloP100		-0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs933271; hg19: chr22-19931407;