22-19969258-G-A

Variant names:

• chr22-19969258-G-A
• rs165599
• NM_000754.4:c.*522G>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.*522G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 154,512 control chromosomes in the GnomAD database, including 26,317 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.56 (25871 hom., cov: 33)
  • Exomes 𝑓: 0.59 (446 hom.)
• Consequence: COMT NM_000754.4 3_prime_UTR
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 0.0760
• Publications: 225 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]

ARVCF (HGNC:728): (ARVCF delta catenin family member) Armadillo Repeat gene deleted in Velo-Cardio-Facial syndrome (ARVCF) is a member of the catenin family. This family plays an important role in the formation of adherens junction complexes, which are thought to facilitate communication between the inside and outside environments of a cell. The ARVCF gene was isolated in the search for the genetic defect responsible for the autosomal dominant Velo-Cardio-Facial syndrome (VCFS), a relatively common human disorder with phenotypic features including cleft palate, conotruncal heart defects and facial dysmorphology. The ARVCF gene encodes a protein containing two motifs, a coiled coil domain in the N-terminus and a 10 armadillo repeat sequence in the midregion. Since these sequences can facilitate protein-protein interactions ARVCF is thought to function in a protein complex. In addition, ARVCF contains a predicted nuclear-targeting sequence suggesting that it may have a function as a nuclear protein. [provided by RefSeq, Jun 2010]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.689 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.*522G>A		3_prime_UTR	Exon 6 of 6	NP_000745.1
	COMT	NM_001135161.2		c.*522G>A		3_prime_UTR	Exon 6 of 6	NP_001128633.1
	COMT	NM_001135162.2		c.*522G>A		3_prime_UTR	Exon 6 of 6	NP_001128634.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	ENST00000361682.11	TSL:1 MANE Select	c.*522G>A		3_prime_UTR	Exon 6 of 6	ENSP00000354511.6
	COMT	ENST00000678769.1		c.*522G>A		3_prime_UTR	Exon 7 of 7	ENSP00000503289.1
	COMT	ENST00000852828.1		c.*522G>A		3_prime_UTR	Exon 7 of 7	ENSP00000522887.1

Frequencies

GnomAD3 genomes AF: 0.560 AC: 85081 AN: 151920 Hom.: 25878 Cov.: 33

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.796

Gnomad AMR AF: 0.541

Gnomad ASJ AF: 0.609

Gnomad EAS AF: 0.499

Gnomad SAS AF: 0.568

Gnomad FIN AF: 0.668

Gnomad MID AF: 0.655

Gnomad NFE AF: 0.694

Gnomad OTH AF: 0.580

GnomAD4 exome AF: 0.589 AC: 1456 AN: 2474 Hom.: 446 Cov.: 0 AF XY: 0.576 AC XY: 794 AN XY: 1378

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.452 AC: 199 AN: 440

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 10 AN: 18

East Asian (EAS) AF: 0.583 AC: 14 AN: 24

South Asian (SAS) AF: 0.474 AC: 93 AN: 196

European-Finnish (FIN) AF: 0.586 AC: 34 AN: 58

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.640 AC: 1053 AN: 1646

Other (OTH) AF: 0.589 AC: 53 AN: 90

GnomAD4 genome AF: 0.560 AC: 85076 AN: 152038 Hom.: 25871 Cov.: 33 AF XY: 0.558 AC XY: 41486 AN XY: 74306

African (AFR) AF: 0.315 AC: 13069 AN: 41470

American (AMR) AF: 0.540 AC: 8248 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.609 AC: 2112 AN: 3470

East Asian (EAS) AF: 0.499 AC: 2568 AN: 5146

South Asian (SAS) AF: 0.567 AC: 2737 AN: 4824

European-Finnish (FIN) AF: 0.668 AC: 7065 AN: 10584

Middle Eastern (MID) AF: 0.656 AC: 193 AN: 294

European-Non Finnish (NFE) AF: 0.694 AC: 47141 AN: 67948

Other (OTH) AF: 0.578 AC: 1220 AN: 2110

Alfa AF: 0.646 Hom.: 127318

Bravo AF: 0.538

Asia WGS AF: 0.531 AC: 1846 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: drug response

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Tramadol response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.8
DANN	Benign	0.47
PhyloP100		0.076
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: rs165599; hg19: chr22-19956781;