rs740603

Variant names:

• chr22-19957654-A-G
• rs740603
• NM_000754.4:c.-91-3545A>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.-91-3545A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 152,124 control chromosomes in the GnomAD database, including 18,028 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 0.48 (18028 hom., cov: 33)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.10
• Publications: 81 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=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4	c.-91-3545A>G		intron_variant	Intron 1 of 5	ENST00000361682.11	NP_000745.1
COMT	NM_001135161.2	c.-91-3545A>G		intron_variant	Intron 1 of 5		NP_001128633.1
COMT	NM_001135162.2	c.-91-3545A>G		intron_variant	Intron 1 of 5		NP_001128634.1
COMT	NM_001362828.2	c.-385-3545A>G		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.-91-3545A>G		intron_variant	Intron 1 of 5	1	NM_000754.4	ENSP00000354511.6

Frequencies

GnomAD3 genomes AF: 0.482 AC: 73303 AN: 152006 Hom.: 18014 Cov.: 33

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.537

Gnomad AMR AF: 0.471

Gnomad ASJ AF: 0.650

Gnomad EAS AF: 0.401

Gnomad SAS AF: 0.520

Gnomad FIN AF: 0.365

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.544

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

GnomAD4 genome AF: 0.482 AC: 73355 AN: 152124 Hom.: 18028 Cov.: 33 AF XY: 0.477 AC XY: 35480 AN XY: 74366

African (AFR) AF: 0.436 AC: 18097 AN: 41478

American (AMR) AF: 0.471 AC: 7197 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.650 AC: 2258 AN: 3472

East Asian (EAS) AF: 0.400 AC: 2068 AN: 5174

South Asian (SAS) AF: 0.520 AC: 2510 AN: 4826

European-Finnish (FIN) AF: 0.365 AC: 3862 AN: 10580

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.523 AC: 35561 AN: 67984

Other (OTH) AF: 0.543 AC: 1149 AN: 2116

Alfa AF: 0.517 Hom.: 76610

Bravo AF: 0.486

Asia WGS AF: 0.459 AC: 1599 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.3
DANN	Benign	0.35
PhyloP100		-3.1
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: rs740603; hg19: chr22-19945177;