22-19968739-GC-GCCC

Variant names:

• chr22-19968739-G-GCC
• rs397758621
• NM_000754.4:c.*9_*10dupCC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000754.4(COMT):​c.*9_*10dupCC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000939 in 1,594,896 control chromosomes in the GnomAD database, including 5 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00096 (5 hom.)
• Consequence: COMT NM_000754.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.06
• Publications: 12 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 115 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000754.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	NM_000754.4	MANE Select	c.*9_*10dupCC		3_prime_UTR	Exon 6 of 6	NP_000745.1	P21964-1
	COMT	NM_001135161.2		c.*9_*10dupCC		3_prime_UTR	Exon 6 of 6	NP_001128633.1	P21964-1
	COMT	NM_001135162.2		c.*9_*10dupCC		3_prime_UTR	Exon 6 of 6	NP_001128634.1	P21964-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	ENST00000361682.11	TSL:1 MANE Select	c.*9_*10dupCC		3_prime_UTR	Exon 6 of 6	ENSP00000354511.6	P21964-1
	COMT	ENST00000406520.7	TSL:1	c.*9_*10dupCC		3_prime_UTR	Exon 6 of 6	ENSP00000385150.3	P21964-1
	COMT	ENST00000449653.5	TSL:1	c.*9_*10dupCC		3_prime_UTR	Exon 4 of 4	ENSP00000416778.1	P21964-2

Frequencies

GnomAD3 genomes AF: 0.000757 AC: 115 AN: 151846 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000583

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00104 AC: 243 AN: 233776 AF XY: 0.00105

Gnomad AFR exome AF: 0.000343

Gnomad AMR exome AF: 0.000831

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.000861

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.000346

GnomAD4 exome AF: 0.000958 AC: 1383 AN: 1442934 Hom.: 5 Cov.: 34 AF XY: 0.00101 AC XY: 722 AN XY: 718016

African (AFR) AF: 0.000631 AC: 21 AN: 33286

American (AMR) AF: 0.000926 AC: 41 AN: 44266

Ashkenazi Jewish (ASJ) AF: 0.0000773 AC: 2 AN: 25870

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39418

South Asian (SAS) AF: 0.00236 AC: 202 AN: 85546

European-Finnish (FIN) AF: 0.000727 AC: 35 AN: 48118

Middle Eastern (MID) AF: 0.00118 AC: 6 AN: 5066

European-Non Finnish (NFE) AF: 0.000937 AC: 1032 AN: 1101720

Other (OTH) AF: 0.000671 AC: 40 AN: 59644

GnomAD4 genome AF: 0.000757 AC: 115 AN: 151962 Hom.: 0 Cov.: 0 AF XY: 0.000727 AC XY: 54 AN XY: 74252

African (AFR) AF: 0.000410 AC: 17 AN: 41444

American (AMR) AF: 0.00105 AC: 16 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000585 AC: 3 AN: 5130

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4818

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 67946

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000686 Hom.: 3961

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397758621; hg19: chr22-19956262;