22-19955157-C-G

Variant names:

• chr22-19955157-C-G
• rs7290221
• NM_000754.4:c.-91-6042C>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.-91-6042C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 152,046 control chromosomes in the GnomAD database, including 19,161 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 0.50 (19161 hom., cov: 33)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.755
• Publications: 10 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.511 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.-91-6042C>G		intron	N/A	NP_000745.1
	COMT	NM_001135161.2		c.-92+4105C>G		intron	N/A	NP_001128633.1
	COMT	NM_001135162.2		c.-92+3503C>G		intron	N/A	NP_001128634.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	ENST00000361682.11	TSL:1 MANE Select	c.-91-6042C>G		intron	N/A	ENSP00000354511.6
	COMT	ENST00000406520.7	TSL:1	c.-92+3503C>G		intron	N/A	ENSP00000385150.3
	COMT	ENST00000678769.1		c.-91-6042C>G		intron	N/A	ENSP00000503289.1

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75624 AN: 151928 Hom.: 19140 Cov.: 33

Gnomad AFR AF: 0.517

Gnomad AMI AF: 0.535

Gnomad AMR AF: 0.468

Gnomad ASJ AF: 0.656

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.359

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.547

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

GnomAD4 genome AF: 0.498 AC: 75688 AN: 152046 Hom.: 19161 Cov.: 33 AF XY: 0.492 AC XY: 36548 AN XY: 74334

African (AFR) AF: 0.517 AC: 21419 AN: 41446

American (AMR) AF: 0.467 AC: 7140 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.656 AC: 2278 AN: 3472

East Asian (EAS) AF: 0.401 AC: 2068 AN: 5162

South Asian (SAS) AF: 0.512 AC: 2472 AN: 4830

European-Finnish (FIN) AF: 0.359 AC: 3793 AN: 10570

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.511 AC: 34707 AN: 67966

Other (OTH) AF: 0.546 AC: 1151 AN: 2108

Alfa AF: 0.329 Hom.: 766

Bravo AF: 0.504

Asia WGS AF: 0.455 AC: 1584 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.2
DANN	Benign	0.67
PhyloP100		0.76
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: rs7290221; hg19: chr22-19942680;