22-19968739-GC-GCC

Variant names:

• chr22-19968739-G-GC
• rs397758621
• NM_000754.4:c.*10dupC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000754.4(COMT):​c.*10dupC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.701 in 1,594,670 control chromosomes in the GnomAD database, including 396,962 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (31467 hom., cov: 0)
  • Exomes 𝑓: 0.71 (365495 hom.)
• Consequence: COMT NM_000754.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 22-19968739-G-GC is Benign according to our data. Variant chr22-19968739-G-GC is described in ClinVar as Benign. ClinVar VariationId is 256784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.732 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4	c.*10dupC		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.*10dupC		3_prime_UTR_variant	Exon 6 of 6	1	NM_000754.4	ENSP00000354511.6

Frequencies

GnomAD3 genomes AF: 0.630 AC: 95592 AN: 151788 Hom.: 31467 Cov.: 0

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.868

Gnomad AMR AF: 0.612

Gnomad ASJ AF: 0.693

Gnomad EAS AF: 0.526

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.690

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.737

Gnomad OTH AF: 0.662

GnomAD2 exomes AF: 0.655 AC: 153113 AN: 233776 AF XY: 0.664

Gnomad AFR exome AF: 0.433

Gnomad AMR exome AF: 0.564

Gnomad ASJ exome AF: 0.678

Gnomad EAS exome AF: 0.528

Gnomad FIN exome AF: 0.677

Gnomad NFE exome AF: 0.732

Gnomad OTH exome AF: 0.687

GnomAD4 exome AF: 0.709 AC: 1022605 AN: 1442766 Hom.: 365495 Cov.: 34 AF XY: 0.708 AC XY: 508283 AN XY: 717936

African (AFR) AF: 0.430 AC: 14318 AN: 33274

American (AMR) AF: 0.568 AC: 25143 AN: 44256

Ashkenazi Jewish (ASJ) AF: 0.680 AC: 17583 AN: 25868

East Asian (EAS) AF: 0.540 AC: 21293 AN: 39410

South Asian (SAS) AF: 0.646 AC: 55234 AN: 85542

European-Finnish (FIN) AF: 0.688 AC: 33097 AN: 48102

Middle Eastern (MID) AF: 0.696 AC: 3524 AN: 5066

European-Non Finnish (NFE) AF: 0.736 AC: 811298 AN: 1101600

Other (OTH) AF: 0.689 AC: 41115 AN: 59648

GnomAD4 genome AF: 0.629 AC: 95601 AN: 151904 Hom.: 31467 Cov.: 0 AF XY: 0.627 AC XY: 46542 AN XY: 74226

African (AFR) AF: 0.441 AC: 18268 AN: 41424

American (AMR) AF: 0.611 AC: 9325 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 2402 AN: 3464

East Asian (EAS) AF: 0.526 AC: 2697 AN: 5128

South Asian (SAS) AF: 0.656 AC: 3162 AN: 4818

European-Finnish (FIN) AF: 0.690 AC: 7284 AN: 10564

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.737 AC: 50074 AN: 67936

Other (OTH) AF: 0.661 AC: 1395 AN: 2112

Alfa AF: 0.635 Hom.: 3961

Bravo AF: 0.610

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
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: rs397758621; hg19: chr22-19956262; COSMIC: COSV52889970; COSMIC: COSV52889970;