rs5746849

Variant names:

• chr22-19955474-A-G
• rs5746849
• NM_000754.4:c.-91-5725A>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.-91-5725A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.503 in 152,182 control chromosomes in the GnomAD database, including 19,551 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 0.50 (19551 hom., cov: 34)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.674
• Publications: 9 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.528 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4	c.-91-5725A>G		intron_variant	Intron 1 of 5	ENST00000361682.11	NP_000745.1
COMT	NM_001135161.2	c.-92+4422A>G		intron_variant	Intron 1 of 5		NP_001128633.1
COMT	NM_001135162.2	c.-92+3820A>G		intron_variant	Intron 1 of 5		NP_001128634.1
COMT	NM_001362828.2	c.-385-5725A>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.-91-5725A>G		intron_variant	Intron 1 of 5	1	NM_000754.4	ENSP00000354511.6

Frequencies

GnomAD3 genomes AF: 0.503 AC: 76442 AN: 152064 Hom.: 19531 Cov.: 34

Gnomad AFR AF: 0.534

Gnomad AMI AF: 0.537

Gnomad AMR AF: 0.468

Gnomad ASJ AF: 0.656

Gnomad EAS AF: 0.401

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.550

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

GnomAD4 genome AF: 0.503 AC: 76505 AN: 152182 Hom.: 19551 Cov.: 34 AF XY: 0.496 AC XY: 36930 AN XY: 74386

African (AFR) AF: 0.534 AC: 22163 AN: 41524

American (AMR) AF: 0.468 AC: 7153 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.656 AC: 2276 AN: 3470

East Asian (EAS) AF: 0.400 AC: 2066 AN: 5166

South Asian (SAS) AF: 0.512 AC: 2470 AN: 4824

European-Finnish (FIN) AF: 0.360 AC: 3807 AN: 10582

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.511 AC: 34746 AN: 67998

Other (OTH) AF: 0.549 AC: 1162 AN: 2116

Alfa AF: 0.504 Hom.: 27861

Bravo AF: 0.509

Asia WGS AF: 0.456 AC: 1587 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.88
DANN	Benign	0.26
PhyloP100		-0.67
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: rs5746849; hg19: chr22-19942997;