22-19969030-C-G

Variant names:

• chr22-19969030-C-G
• rs9332381
• NM_000754.4:c.*294C>G

Variant summary

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

The NM_000754.4(COMT):​c.*294C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0767 in 297,176 control chromosomes in the GnomAD database, including 1,679 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 0.10 (1391 hom., cov: 33)
  • Exomes 𝑓: 0.052 (288 hom.)
• Consequence: COMT NM_000754.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.16
• Publications: 7 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4	c.*294C>G		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.*294C>G		3_prime_UTR_variant	Exon 6 of 6	1	NM_000754.4	ENSP00000354511.6

Frequencies

GnomAD3 genomes AF: 0.100 AC: 15282 AN: 152132 Hom.: 1385 Cov.: 33

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0588

Gnomad ASJ AF: 0.0302

Gnomad EAS AF: 0.0679

Gnomad SAS AF: 0.0656

Gnomad FIN AF: 0.0524

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0410

Gnomad OTH AF: 0.0844

GnomAD4 exome AF: 0.0516 AC: 7477 AN: 144926 Hom.: 288 Cov.: 0 AF XY: 0.0519 AC XY: 4065 AN XY: 78330

African (AFR) AF: 0.233 AC: 982 AN: 4216

American (AMR) AF: 0.0490 AC: 309 AN: 6312

Ashkenazi Jewish (ASJ) AF: 0.0314 AC: 131 AN: 4174

East Asian (EAS) AF: 0.0545 AC: 369 AN: 6766

South Asian (SAS) AF: 0.0640 AC: 1513 AN: 23634

European-Finnish (FIN) AF: 0.0417 AC: 256 AN: 6132

Middle Eastern (MID) AF: 0.0320 AC: 17 AN: 532

European-Non Finnish (NFE) AF: 0.0409 AC: 3500 AN: 85588

Other (OTH) AF: 0.0528 AC: 400 AN: 7572

GnomAD4 genome AF: 0.101 AC: 15309 AN: 152250 Hom.: 1391 Cov.: 33 AF XY: 0.0992 AC XY: 7385 AN XY: 74430

African (AFR) AF: 0.243 AC: 10102 AN: 41520

American (AMR) AF: 0.0591 AC: 905 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0302 AC: 105 AN: 3472

East Asian (EAS) AF: 0.0680 AC: 353 AN: 5190

South Asian (SAS) AF: 0.0657 AC: 317 AN: 4826

European-Finnish (FIN) AF: 0.0524 AC: 556 AN: 10606

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0410 AC: 2788 AN: 68018

Other (OTH) AF: 0.0835 AC: 176 AN: 2108

Alfa AF: 0.0726 Hom.: 117

Bravo AF: 0.107

Asia WGS AF: 0.0600 AC: 208 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.13
DANN	Benign	0.43
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: rs9332381; hg19: chr22-19956553;