rs5993883

Variant names:

• chr22-19950115-T-G
• rs5993883
• NM_000754.4:c.-92+8218T>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+8218T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 151,912 control chromosomes in the GnomAD database, including 18,706 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 0.49 (18706 hom., cov: 32)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.402
• Publications: 58 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=-1.01).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.512 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+8218T>G		intron	N/A	NP_000745.1
	COMT	NM_001362828.2		c.-386+8218T>G		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+8218T>G		intron	N/A	ENSP00000354511.6
	COMT	ENST00000678769.1		c.-92+8218T>G		intron	N/A	ENSP00000503289.1
	COMT	ENST00000428707.2	TSL:3	c.-92+8218T>G		intron	N/A	ENSP00000387695.2

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74591 AN: 151794 Hom.: 18692 Cov.: 32

Gnomad AFR AF: 0.486

Gnomad AMI AF: 0.537

Gnomad AMR AF: 0.471

Gnomad ASJ AF: 0.675

Gnomad EAS AF: 0.375

Gnomad SAS AF: 0.505

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.517

Gnomad OTH AF: 0.538

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

GnomAD4 genome AF: 0.491 AC: 74644 AN: 151912 Hom.: 18706 Cov.: 32 AF XY: 0.485 AC XY: 36009 AN XY: 74270

African (AFR) AF: 0.486 AC: 20148 AN: 41462

American (AMR) AF: 0.470 AC: 7177 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.675 AC: 2340 AN: 3466

East Asian (EAS) AF: 0.375 AC: 1944 AN: 5188

South Asian (SAS) AF: 0.505 AC: 2432 AN: 4820

European-Finnish (FIN) AF: 0.356 AC: 3733 AN: 10484

Middle Eastern (MID) AF: 0.524 AC: 153 AN: 292

European-Non Finnish (NFE) AF: 0.517 AC: 35099 AN: 67920

Other (OTH) AF: 0.537 AC: 1128 AN: 2102

Alfa AF: 0.515 Hom.: 87136

Bravo AF: 0.498

Asia WGS AF: 0.431 AC: 1500 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.0
DANN	Benign	0.36
PhyloP100		-0.40
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: rs5993883; hg19: chr22-19937638;