chr22-19942598-A-G

Variant names:

• chr22-19942598-A-G
• rs737865
• NM_000754.4:c.-92+701A>G

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+701A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 152,086 control chromosomes in the GnomAD database, including 4,399 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 0.23 (4399 hom., cov: 32)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.200
• Publications: 170 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.275 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	NM_000754.4	MANE Select	c.-92+701A>G		intron	N/A	NP_000745.1
	COMT	NM_001362828.2		c.-386+701A>G		intron	N/A	NP_001349757.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	ENST00000361682.11	TSL:1 MANE Select	c.-92+701A>G		intron	N/A	ENSP00000354511.6
	COMT	ENST00000678769.1		c.-92+701A>G		intron	N/A	ENSP00000503289.1
	COMT	ENST00000428707.2	TSL:3	c.-92+701A>G		intron	N/A	ENSP00000387695.2

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35389 AN: 151968 Hom.: 4398 Cov.: 32

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.427

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.256

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

GnomAD4 genome AF: 0.233 AC: 35403 AN: 152086 Hom.: 4399 Cov.: 32 AF XY: 0.231 AC XY: 17154 AN XY: 74320

African (AFR) AF: 0.149 AC: 6186 AN: 41496

American (AMR) AF: 0.220 AC: 3362 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.427 AC: 1483 AN: 3472

East Asian (EAS) AF: 0.273 AC: 1406 AN: 5156

South Asian (SAS) AF: 0.263 AC: 1270 AN: 4824

European-Finnish (FIN) AF: 0.187 AC: 1978 AN: 10572

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.278 AC: 18927 AN: 67968

Other (OTH) AF: 0.257 AC: 541 AN: 2108

Alfa AF: 0.266 Hom.: 16061

Bravo AF: 0.228

Asia WGS AF: 0.271 AC: 944 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.3
DANN	Benign	0.79
PhyloP100		-0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		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: rs737865; hg19: chr22-19930121;