22-19955157-C-G

Position:

• chr22-19955157-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000754.4(COMT):​c.-91-6042C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 152,046 control chromosomes in the GnomAD database, including 19,161 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 (19161 hom., cov: 33)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.755

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COMT	NM_000754.4	c.-91-6042C>G		intron_variant		ENST00000361682.11	NP_000745.1
COMT	NM_001135161.2	c.-92+4105C>G		intron_variant			NP_001128633.1
COMT	NM_001135162.2	c.-92+3503C>G		intron_variant			NP_001128634.1
COMT	NM_001362828.2	c.-385-6042C>G		intron_variant			NP_001349757.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COMT	ENST00000361682.11	c.-91-6042C>G		intron_variant		1	NM_000754.4	ENSP00000354511	P2

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75624 AN: 151928 Hom.: 19140 Cov.: 33

Gnomad AFR AF: 0.517

Gnomad AMI AF: 0.535

Gnomad AMR AF: 0.468

Gnomad ASJ AF: 0.656

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.359

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.547

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

GnomAD4 genome AF: 0.498 AC: 75688 AN: 152046 Hom.: 19161 Cov.: 33 AF XY: 0.492 AC XY: 36548 AN XY: 74334

Gnomad4 AFR AF: 0.517

Gnomad4 AMR AF: 0.467

Gnomad4 ASJ AF: 0.656

Gnomad4 EAS AF: 0.401

Gnomad4 SAS AF: 0.512

Gnomad4 FIN AF: 0.359

Gnomad4 NFE AF: 0.511

Gnomad4 OTH AF: 0.546

Alfa AF: 0.329 Hom.: 766

Bravo AF: 0.504

Asia WGS AF: 0.455 AC: 1584 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.2
DANN	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs7290221; hg19: chr22-19942680;