rs165774

Variant names:

• chr22-19965038-G-A
• rs165774
• NM_000754.4:c.615+739G>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.615+739G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 163,790 control chromosomes in the GnomAD database, including 5,986 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 0.27 (5639 hom., cov: 33)
  • Exomes 𝑓: 0.22 (347 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.368
• Publications: 64 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4	c.615+739G>A		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+739G>A		intron_variant	Intron 5 of 5	1	NM_000754.4	ENSP00000354511.6

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40363 AN: 152074 Hom.: 5636 Cov.: 33

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.409

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.262

GnomAD4 exome AF: 0.220 AC: 2551 AN: 11596 Hom.: 347 Cov.: 0 AF XY: 0.222 AC XY: 1328 AN XY: 5992

African (AFR) AF: 0.155 AC: 30 AN: 194

American (AMR) AF: 0.178 AC: 485 AN: 2726

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 23 AN: 98

East Asian (EAS) AF: 0.0746 AC: 47 AN: 630

South Asian (SAS) AF: 0.156 AC: 217 AN: 1392

European-Finnish (FIN) AF: 0.192 AC: 25 AN: 130

Middle Eastern (MID) AF: 0.300 AC: 6 AN: 20

European-Non Finnish (NFE) AF: 0.270 AC: 1595 AN: 5916

Other (OTH) AF: 0.251 AC: 123 AN: 490

GnomAD4 genome AF: 0.265 AC: 40370 AN: 152194 Hom.: 5639 Cov.: 33 AF XY: 0.261 AC XY: 19384 AN XY: 74394

African (AFR) AF: 0.219 AC: 9079 AN: 41532

American (AMR) AF: 0.213 AC: 3261 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 1105 AN: 3472

East Asian (EAS) AF: 0.139 AC: 722 AN: 5180

South Asian (SAS) AF: 0.197 AC: 952 AN: 4822

European-Finnish (FIN) AF: 0.250 AC: 2650 AN: 10588

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.318 AC: 21588 AN: 67982

Other (OTH) AF: 0.261 AC: 551 AN: 2110

Alfa AF: 0.296 Hom.: 6214

Bravo AF: 0.260

Asia WGS AF: 0.177 AC: 616 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.47
PhyloP100		-0.37
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: rs165774; hg19: chr22-19952561;