rs174699

Variant names:

• chr22-19966935-C-T
• rs174699
• NM_000754.4:c.616-1601C>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.616-1601C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.941 in 985,194 control chromosomes in the GnomAD database, including 436,956 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 0.92 (64811 hom., cov: 31)
  • Exomes 𝑓: 0.94 (372145 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.861
• Publications: 35 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 = 0.958 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4	c.616-1601C>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.616-1601C>T		intron_variant	Intron 5 of 5	1	NM_000754.4	ENSP00000354511.6

Frequencies

GnomAD3 genomes AF: 0.919 AC: 139757 AN: 152082 Hom.: 64765 Cov.: 31

Gnomad AFR AF: 0.966

Gnomad AMI AF: 0.976

Gnomad AMR AF: 0.820

Gnomad ASJ AF: 0.959

Gnomad EAS AF: 0.597

Gnomad SAS AF: 0.889

Gnomad FIN AF: 0.862

Gnomad MID AF: 0.959

Gnomad NFE AF: 0.945

Gnomad OTH AF: 0.926

GnomAD4 exome AF: 0.945 AC: 786932 AN: 832994 Hom.: 372145 Cov.: 29 AF XY: 0.945 AC XY: 363597 AN XY: 384676

African (AFR) AF: 0.972 AC: 15339 AN: 15784

American (AMR) AF: 0.749 AC: 737 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.956 AC: 4923 AN: 5150

East Asian (EAS) AF: 0.580 AC: 2106 AN: 3628

South Asian (SAS) AF: 0.892 AC: 14671 AN: 16452

European-Finnish (FIN) AF: 0.873 AC: 241 AN: 276

Middle Eastern (MID) AF: 0.958 AC: 1552 AN: 1620

European-Non Finnish (NFE) AF: 0.948 AC: 722271 AN: 761804

Other (OTH) AF: 0.919 AC: 25092 AN: 27296

GnomAD4 genome AF: 0.919 AC: 139854 AN: 152200 Hom.: 64811 Cov.: 31 AF XY: 0.911 AC XY: 67805 AN XY: 74412

African (AFR) AF: 0.966 AC: 40121 AN: 41532

American (AMR) AF: 0.819 AC: 12513 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.959 AC: 3328 AN: 3470

East Asian (EAS) AF: 0.597 AC: 3088 AN: 5170

South Asian (SAS) AF: 0.888 AC: 4281 AN: 4820

European-Finnish (FIN) AF: 0.862 AC: 9119 AN: 10582

Middle Eastern (MID) AF: 0.963 AC: 283 AN: 294

European-Non Finnish (NFE) AF: 0.945 AC: 64276 AN: 68022

Other (OTH) AF: 0.924 AC: 1955 AN: 2116

Alfa AF: 0.930 Hom.: 218588

Bravo AF: 0.914

Asia WGS AF: 0.759 AC: 2642 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	0.43
DANN	Benign	0.66
PhyloP100		-0.86
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: rs174699; hg19: chr22-19954458;