22-19965653-C-T

Variant names:

• chr22-19965653-C-T
• rs174696
• NM_000754.4:c.615+1354C>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.615+1354C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 151,462 control chromosomes in the GnomAD database, including 31,662 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 0.63 (31622 hom., cov: 34)
  • Exomes 𝑓: 0.76 (40 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40
• Publications: 38 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=-1.01).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4	c.615+1354C>T		intron_variant	Intron 5 of 5	ENST00000361682.11	NP_000745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COMT	ENST00000361682.11	c.615+1354C>T		intron_variant	Intron 5 of 5	1	NM_000754.4	ENSP00000354511.6

Frequencies

GnomAD3 genomes AF: 0.626 AC: 94638 AN: 151202 Hom.: 31626 Cov.: 34

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.724

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.833

Gnomad EAS AF: 0.461

Gnomad SAS AF: 0.550

Gnomad FIN AF: 0.638

Gnomad MID AF: 0.748

Gnomad NFE AF: 0.777

Gnomad OTH AF: 0.654

GnomAD4 exome AF: 0.757 AC: 106 AN: 140 Hom.: 40 Cov.: 0 AF XY: 0.765 AC XY: 78 AN XY: 102

African (AFR) AF: 0.500 AC: 2 AN: 4

American (AMR) AF: 1.00 AC: 4 AN: 4

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 3 AN: 6

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.800 AC: 88 AN: 110

Other (OTH) AF: 0.750 AC: 6 AN: 8

GnomAD4 genome AF: 0.625 AC: 94645 AN: 151322 Hom.: 31622 Cov.: 34 AF XY: 0.618 AC XY: 45685 AN XY: 73964

African (AFR) AF: 0.412 AC: 17048 AN: 41372

American (AMR) AF: 0.543 AC: 8256 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.833 AC: 2883 AN: 3462

East Asian (EAS) AF: 0.460 AC: 2380 AN: 5170

South Asian (SAS) AF: 0.549 AC: 2643 AN: 4810

European-Finnish (FIN) AF: 0.638 AC: 6661 AN: 10438

Middle Eastern (MID) AF: 0.753 AC: 220 AN: 292

European-Non Finnish (NFE) AF: 0.777 AC: 52539 AN: 67592

Other (OTH) AF: 0.653 AC: 1372 AN: 2102

Alfa AF: 0.663 Hom.: 18862

Bravo AF: 0.606

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.47
DANN	Benign	0.51
PhyloP100		-1.4
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: rs174696; hg19: chr22-19953176;