rs165737

Variant names:

• chr22-19964978-C-T
• rs165737
• NM_000754.4:c.615+679C>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+679C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 171,456 control chromosomes in the GnomAD database, including 6,369 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 (5723 hom., cov: 33)
  • Exomes 𝑓: 0.23 (646 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0970
• Publications: 3 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=-0.87).
• 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+679C>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+679C>T		intron_variant	Intron 5 of 5	1	NM_000754.4	ENSP00000354511.6

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40717 AN: 152036 Hom.: 5720 Cov.: 33

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.409

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.264

GnomAD4 exome AF: 0.233 AC: 4504 AN: 19302 Hom.: 646 Cov.: 0 AF XY: 0.233 AC XY: 2347 AN XY: 10090

African (AFR) AF: 0.195 AC: 105 AN: 538

American (AMR) AF: 0.193 AC: 631 AN: 3270

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 74 AN: 240

East Asian (EAS) AF: 0.0946 AC: 123 AN: 1300

South Asian (SAS) AF: 0.172 AC: 429 AN: 2500

European-Finnish (FIN) AF: 0.189 AC: 73 AN: 386

Middle Eastern (MID) AF: 0.292 AC: 14 AN: 48

European-Non Finnish (NFE) AF: 0.280 AC: 2851 AN: 10194

Other (OTH) AF: 0.247 AC: 204 AN: 826

GnomAD4 genome AF: 0.268 AC: 40724 AN: 152154 Hom.: 5723 Cov.: 33 AF XY: 0.263 AC XY: 19579 AN XY: 74422

African (AFR) AF: 0.226 AC: 9379 AN: 41520

American (AMR) AF: 0.215 AC: 3290 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 1104 AN: 3472

East Asian (EAS) AF: 0.140 AC: 722 AN: 5174

South Asian (SAS) AF: 0.199 AC: 958 AN: 4818

European-Finnish (FIN) AF: 0.250 AC: 2651 AN: 10610

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.318 AC: 21605 AN: 67950

Other (OTH) AF: 0.263 AC: 554 AN: 2106

Alfa AF: 0.291 Hom.: 2395

Bravo AF: 0.262

Asia WGS AF: 0.178 AC: 619 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.4
DANN	Benign	0.79
PhyloP100		-0.097
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs165737; hg19: chr22-19952501;