rs174674

Variant names:

• chr22-19946502-A-G
• rs174674
• NM_000754.4:c.-92+4605A>G

Your query was ambiguous. Multiple possible variants found:

• chr22-19946502-A-G
• chr22-19946502-A-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.-92+4605A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 151,956 control chromosomes in the GnomAD database, including 34,855 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 0.67 (34855 hom., cov: 31)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.118
• Publications: 22 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=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.712 is higher than 0.05.

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.-92+4605A>G		intron	N/A	NP_000745.1	P21964-1
	COMT	NM_001362828.2		c.-386+4605A>G		intron	N/A	NP_001349757.1	P21964-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	ENST00000361682.11	TSL:1 MANE Select	c.-92+4605A>G		intron	N/A	ENSP00000354511.6	P21964-1
	COMT	ENST00000964897.1		c.-92+4605A>G		intron	N/A	ENSP00000634956.1
	COMT	ENST00000678769.1		c.-92+4605A>G		intron	N/A	ENSP00000503289.1	A0A7I2V370

Frequencies

GnomAD3 genomes AF: 0.675 AC: 102492 AN: 151838 Hom.: 34844 Cov.: 31

Gnomad AFR AF: 0.651

Gnomad AMI AF: 0.674

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.715

Gnomad EAS AF: 0.564

Gnomad SAS AF: 0.627

Gnomad FIN AF: 0.708

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.717

Gnomad OTH AF: 0.654

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

GnomAD4 genome AF: 0.675 AC: 102550 AN: 151956 Hom.: 34855 Cov.: 31 AF XY: 0.670 AC XY: 49771 AN XY: 74248

African (AFR) AF: 0.650 AC: 26928 AN: 41406

American (AMR) AF: 0.575 AC: 8783 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.715 AC: 2478 AN: 3468

East Asian (EAS) AF: 0.564 AC: 2905 AN: 5152

South Asian (SAS) AF: 0.627 AC: 3022 AN: 4818

European-Finnish (FIN) AF: 0.708 AC: 7477 AN: 10560

Middle Eastern (MID) AF: 0.769 AC: 226 AN: 294

European-Non Finnish (NFE) AF: 0.717 AC: 48738 AN: 67966

Other (OTH) AF: 0.653 AC: 1378 AN: 2110

Alfa AF: 0.697 Hom.: 49725

Bravo AF: 0.660

Asia WGS AF: 0.606 AC: 2107 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.9
DANN	Benign	0.84
PhyloP100		0.12
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: rs174674; hg19: chr22-19934025;