rs4646312

Variant names:

• chr22-19960814-T-C
• rs4646312
• NM_000754.4:c.-91-385T>C

Variant summary

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

The NM_000754.4(COMT):​c.-91-385T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 152,256 control chromosomes in the GnomAD database, including 8,203 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 0.31 (8203 hom., cov: 34)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.278
• Publications: 60 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]

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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.391 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4	c.-91-385T>C		intron_variant	Intron 1 of 5	ENST00000361682.11	NP_000745.1
COMT	NM_001135161.2	c.-91-385T>C		intron_variant	Intron 1 of 5		NP_001128633.1
COMT	NM_001135162.2	c.-91-385T>C		intron_variant	Intron 1 of 5		NP_001128634.1
COMT	NM_001362828.2	c.-385-385T>C		intron_variant	Intron 1 of 5		NP_001349757.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COMT	ENST00000361682.11	c.-91-385T>C		intron_variant	Intron 1 of 5	1	NM_000754.4	ENSP00000354511.6

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47736 AN: 152138 Hom.: 8211 Cov.: 34

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.471

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.301

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.346

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.313 AC: 47729 AN: 152256 Hom.: 8203 Cov.: 34 AF XY: 0.311 AC XY: 23119 AN XY: 74444

African (AFR) AF: 0.170 AC: 7073 AN: 41564

American (AMR) AF: 0.302 AC: 4627 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 1634 AN: 3472

East Asian (EAS) AF: 0.323 AC: 1671 AN: 5178

South Asian (SAS) AF: 0.311 AC: 1502 AN: 4824

European-Finnish (FIN) AF: 0.301 AC: 3201 AN: 10618

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.395 AC: 26873 AN: 67982

Other (OTH) AF: 0.346 AC: 732 AN: 2114

Alfa AF: 0.364 Hom.: 32120

Bravo AF: 0.306

Asia WGS AF: 0.310 AC: 1080 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.8
DANN	Benign	0.84
PhyloP100		0.28
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4646312; hg19: chr22-19948337;