22-19944453-T-C

Variant names:

• chr22-19944453-T-C
• rs7287550
• NM_000754.4:c.-92+2556T>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+2556T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 151,440 control chromosomes in the GnomAD database, including 8,254 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 0.33 (8254 hom., cov: 31)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.706
• Publications: 6 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 (EAS) allele frequency at 95% confidence interval = 0.423 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+2556T>C		intron	N/A	NP_000745.1
	COMT	NM_001362828.2		c.-386+2556T>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+2556T>C		intron	N/A	ENSP00000354511.6
	COMT	ENST00000678769.1		c.-92+2556T>C		intron	N/A	ENSP00000503289.1
	COMT	ENST00000428707.2	TSL:3	c.-92+2556T>C		intron	N/A	ENSP00000387695.2

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49279 AN: 151322 Hom.: 8241 Cov.: 31

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.424

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.438

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.347

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

GnomAD4 genome AF: 0.326 AC: 49340 AN: 151440 Hom.: 8254 Cov.: 31 AF XY: 0.330 AC XY: 24451 AN XY: 74004

African (AFR) AF: 0.352 AC: 14472 AN: 41172

American (AMR) AF: 0.425 AC: 6473 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 985 AN: 3468

East Asian (EAS) AF: 0.438 AC: 2242 AN: 5118

South Asian (SAS) AF: 0.373 AC: 1786 AN: 4790

European-Finnish (FIN) AF: 0.294 AC: 3075 AN: 10472

Middle Eastern (MID) AF: 0.231 AC: 67 AN: 290

European-Non Finnish (NFE) AF: 0.283 AC: 19210 AN: 67876

Other (OTH) AF: 0.348 AC: 733 AN: 2106

Alfa AF: 0.582 Hom.: 7390

Bravo AF: 0.339

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	-1.0
CADD	Benign	2.6
DANN	Benign	0.36
PhyloP100		-0.71
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: rs7287550; hg19: chr22-19931976;