rs739368

Positions:

• chr22-19951573-G-A

Variant summary

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

The ENST00000406520.7(COMT):​c.-173G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0545 in 152,224 control chromosomes in the GnomAD database, including 722 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 0.054 (722 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COMT ENST00000406520.7 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.297

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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMT	NM_000754.4	c.-91-9626G>A		intron_variant		ENST00000361682.11
COMT	NM_001135162.2	c.-173G>A		5_prime_UTR_variant	1/6
COMT	NM_001135161.2	c.-92+521G>A		intron_variant
COMT	NM_001362828.2	c.-385-9626G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMT	ENST00000361682.11	c.-91-9626G>A		intron_variant		1	NM_000754.4	P2

Frequencies

GnomAD3 genomes AF: 0.0543 AC: 8266 AN: 152106 Hom.: 718 Cov.: 32

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0200

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00165

Gnomad OTH AF: 0.0441

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 42 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 22

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0545 AC: 8296 AN: 152224 Hom.: 722 Cov.: 32 AF XY: 0.0522 AC XY: 3883 AN XY: 74430

Gnomad4 AFR AF: 0.187

Gnomad4 AMR AF: 0.0199

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00165

Gnomad4 OTH AF: 0.0436

Alfa AF: 0.0123 Hom.: 223

Bravo AF: 0.0622

Asia WGS AF: 0.0170 AC: 58 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.0
DANN	Benign	0.63

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: rs739368; hg19: chr22-19939096;