chr22-19970108-C-A

Variant names:

• chr22-19970108-C-A
• rs9265
• NM_001670.3:c.*648G>T

Variant summary

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

The NM_001670.3(ARVCF):​c.*648G>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 0.665 in 985,340 control chromosomes in the GnomAD database, including 223,113 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 0.56 (25905 hom., cov: 32)
  • Exomes 𝑓: 0.68 (197208 hom.)
• Consequence: ARVCF NM_001670.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0890
• Publications: 13 publications found

Genes affected

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]

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]

COMT Gene-Disease associations (from GenCC):

• paroxysmal dyskinesia

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.689 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARVCF	NM_001670.3	c.*648G>T		3_prime_UTR_variant	Exon 20 of 20	ENST00000263207.8	NP_001661.1
COMT	NM_000754.4	c.*1372C>A		downstream_gene_variant		ENST00000361682.11	NP_000745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARVCF	ENST00000263207.8	c.*648G>T		3_prime_UTR_variant	Exon 20 of 20	1	NM_001670.3	ENSP00000263207.3
COMT	ENST00000361682.11	c.*1372C>A		downstream_gene_variant		1	NM_000754.4	ENSP00000354511.6

Frequencies

GnomAD3 genomes AF: 0.560 AC: 85124 AN: 151922 Hom.: 25912 Cov.: 32

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.796

Gnomad AMR AF: 0.541

Gnomad ASJ AF: 0.609

Gnomad EAS AF: 0.497

Gnomad SAS AF: 0.567

Gnomad FIN AF: 0.666

Gnomad MID AF: 0.656

Gnomad NFE AF: 0.694

Gnomad OTH AF: 0.581

GnomAD4 exome AF: 0.685 AC: 570500 AN: 833300 Hom.: 197208 Cov.: 60 AF XY: 0.685 AC XY: 263644 AN XY: 384838

African (AFR) AF: 0.288 AC: 4547 AN: 15788

American (AMR) AF: 0.505 AC: 497 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.596 AC: 3069 AN: 5152

East Asian (EAS) AF: 0.490 AC: 1780 AN: 3632

South Asian (SAS) AF: 0.550 AC: 9053 AN: 16472

European-Finnish (FIN) AF: 0.662 AC: 221 AN: 334

Middle Eastern (MID) AF: 0.615 AC: 998 AN: 1622

European-Non Finnish (NFE) AF: 0.699 AC: 532879 AN: 762016

Other (OTH) AF: 0.639 AC: 17456 AN: 27300

GnomAD4 genome AF: 0.560 AC: 85119 AN: 152040 Hom.: 25905 Cov.: 32 AF XY: 0.558 AC XY: 41498 AN XY: 74310

African (AFR) AF: 0.316 AC: 13094 AN: 41490

American (AMR) AF: 0.540 AC: 8256 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.609 AC: 2112 AN: 3466

East Asian (EAS) AF: 0.497 AC: 2544 AN: 5118

South Asian (SAS) AF: 0.567 AC: 2736 AN: 4826

European-Finnish (FIN) AF: 0.666 AC: 7058 AN: 10592

Middle Eastern (MID) AF: 0.658 AC: 192 AN: 292

European-Non Finnish (NFE) AF: 0.694 AC: 47180 AN: 67944

Other (OTH) AF: 0.580 AC: 1223 AN: 2110

Alfa AF: 0.661 Hom.: 31425

Bravo AF: 0.539

Asia WGS AF: 0.529 AC: 1842 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.9
DANN	Benign	0.68
PhyloP100		0.089
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)		0.030		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: rs9265; hg19: chr22-19957631;