22-19950010-T-G

Position:

• chr22-19950010-T-G

Variant summary

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

The NM_000754.4(COMT):​c.-92+8113T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 152,018 control chromosomes in the GnomAD database, including 5,168 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 0.25 (5168 hom., cov: 32)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.600

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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMT	NM_000754.4	c.-92+8113T>G		intron_variant		ENST00000361682.11
COMT	NM_001362828.2	c.-386+8113T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMT	ENST00000361682.11	c.-92+8113T>G		intron_variant		1	NM_000754.4	P2

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38409 AN: 151900 Hom.: 5163 Cov.: 32

Gnomad AFR AF: 0.328

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.232

Gnomad OTH AF: 0.275

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

GnomAD4 genome AF: 0.253 AC: 38457 AN: 152018 Hom.: 5168 Cov.: 32 AF XY: 0.249 AC XY: 18529 AN XY: 74294

Gnomad4 AFR AF: 0.329

Gnomad4 AMR AF: 0.245

Gnomad4 ASJ AF: 0.245

Gnomad4 EAS AF: 0.114

Gnomad4 SAS AF: 0.246

Gnomad4 FIN AF: 0.170

Gnomad4 NFE AF: 0.232

Gnomad4 OTH AF: 0.274

Alfa AF: 0.147 Hom.: 315

Bravo AF: 0.264

Asia WGS AF: 0.173 AC: 602 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.52
DANN	Benign	0.53

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: rs5993882; hg19: chr22-19937533;