22-19969500-C-T

Variant names:

• chr22-19969500-C-T
• rs165728
• NM_000754.4:c.*764C>T

Variant summary

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

The NM_000754.4(COMT):​c.*764C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.914 in 152,212 control chromosomes in the GnomAD database, including 64,060 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 0.91 (64025 hom., cov: 31)
  • Exomes 𝑓: 0.94 (35 hom.)
• Consequence: COMT NM_000754.4 3_prime_UTR
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -1.24
• Publications: 27 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.941 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4	c.*764C>T		3_prime_UTR_variant	Exon 6 of 6	ENST00000361682.11	NP_000745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COMT	ENST00000361682.11	c.*764C>T		3_prime_UTR_variant	Exon 6 of 6	1	NM_000754.4	ENSP00000354511.6

Frequencies

GnomAD3 genomes AF: 0.914 AC: 138936 AN: 152016 Hom.: 63987 Cov.: 31

Gnomad AFR AF: 0.944

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.816

Gnomad ASJ AF: 0.962

Gnomad EAS AF: 0.601

Gnomad SAS AF: 0.881

Gnomad FIN AF: 0.870

Gnomad MID AF: 0.943

Gnomad NFE AF: 0.947

Gnomad OTH AF: 0.920

GnomAD4 exome AF: 0.936 AC: 73 AN: 78 Hom.: 35 Cov.: 0 AF XY: 0.920 AC XY: 46 AN XY: 50

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 1.00 AC: 6 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.939 AC: 62 AN: 66

Other (OTH) AF: 0.833 AC: 5 AN: 6

GnomAD4 genome AF: 0.914 AC: 139024 AN: 152134 Hom.: 64025 Cov.: 31 AF XY: 0.906 AC XY: 67377 AN XY: 74354

African (AFR) AF: 0.944 AC: 39171 AN: 41512

American (AMR) AF: 0.815 AC: 12452 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.962 AC: 3339 AN: 3472

East Asian (EAS) AF: 0.601 AC: 3105 AN: 5164

South Asian (SAS) AF: 0.880 AC: 4221 AN: 4794

European-Finnish (FIN) AF: 0.870 AC: 9217 AN: 10592

Middle Eastern (MID) AF: 0.949 AC: 279 AN: 294

European-Non Finnish (NFE) AF: 0.947 AC: 64392 AN: 67998

Other (OTH) AF: 0.918 AC: 1937 AN: 2110

Alfa AF: 0.932 Hom.: 177751

Bravo AF: 0.907

Asia WGS AF: 0.753 AC: 2623 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Tramadol response Other:1

Apr 28, 2018

Bruce Budowle Laboratory, University of North Texas Health Science Center

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

- T:M1 = postmortem ratio or tramadol to O-desmethyltramadol; t-MP = model-based clustered metabolizer phenotype inferred from T:M1

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.60
DANN	Benign	0.31
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs165728; hg19: chr22-19957023;