chr22-19960419-C-A

Variant names:

• chr22-19960419-C-A
• rs16982844
• NM_000754.4:c.-91-780C>A

Variant summary

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

The NM_000754.4(COMT):​c.-91-780C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.042 in 152,340 control chromosomes in the GnomAD database, including 208 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 0.042 (208 hom., cov: 33)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.01
• Publications: 8 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0689 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	NM_000754.4	MANE Select	c.-91-780C>A		intron	N/A	NP_000745.1	P21964-1
	COMT	NM_001135161.2		c.-91-780C>A		intron	N/A	NP_001128633.1	P21964-1
	COMT	NM_001135162.2		c.-91-780C>A		intron	N/A	NP_001128634.1	P21964-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	ENST00000361682.11	TSL:1 MANE Select	c.-91-780C>A		intron	N/A	ENSP00000354511.6	P21964-1
	COMT	ENST00000406520.7	TSL:1	c.-91-780C>A		intron	N/A	ENSP00000385150.3	P21964-1
	COMT	ENST00000964897.1		c.-91-780C>A		intron	N/A	ENSP00000634956.1

Frequencies

GnomAD3 genomes AF: 0.0420 AC: 6398 AN: 152222 Hom.: 209 Cov.: 33

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.0203

Gnomad ASJ AF: 0.0279

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.0510

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0706

Gnomad OTH AF: 0.0253

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

GnomAD4 genome AF: 0.0420 AC: 6395 AN: 152340 Hom.: 208 Cov.: 33 AF XY: 0.0390 AC XY: 2909 AN XY: 74496

African (AFR) AF: 0.0114 AC: 473 AN: 41582

American (AMR) AF: 0.0203 AC: 311 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0279 AC: 97 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0122 AC: 59 AN: 4826

European-Finnish (FIN) AF: 0.0510 AC: 541 AN: 10616

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0706 AC: 4804 AN: 68032

Other (OTH) AF: 0.0251 AC: 53 AN: 2114

Alfa AF: 0.0576 Hom.: 44

Bravo AF: 0.0386

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.77
DANN	Benign	0.70
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs16982844; hg19: chr22-19947942;