22-19951573-G-A

Variant names:

• chr22-19951573-G-A
• rs739368
• ENST00000406520.7:c.-173G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000406520.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	NM_000754.4	MANE Select	c.-91-9626G>A		intron	N/A	NP_000745.1
	COMT	NM_001135162.2		c.-173G>A		5_prime_UTR	Exon 1 of 6	NP_001128634.1
	COMT	NM_001135161.2		c.-92+521G>A		intron	N/A	NP_001128633.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	ENST00000406520.7	TSL:1	c.-173G>A		5_prime_UTR	Exon 1 of 6	ENSP00000385150.3
	COMT	ENST00000361682.11	TSL:1 MANE Select	c.-91-9626G>A		intron	N/A	ENSP00000354511.6
	COMT	ENST00000678769.1		c.-91-9626G>A		intron	N/A	ENSP00000503289.1

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 20

Other (OTH) AF: 0.00 AC: 0 AN: 14

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

African (AFR) AF: 0.187 AC: 7764 AN: 41498

American (AMR) AF: 0.0199 AC: 305 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00165 AC: 112 AN: 68026

Other (OTH) AF: 0.0436 AC: 92 AN: 2110

Alfa AF: 0.0233 Hom.: 684

Bravo AF: 0.0622

Asia WGS AF: 0.0170 AC: 58 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.0
DANN	Benign	0.63
PhyloP100		-0.30
PromoterAI		-0.055	Neutral
Mutation Taster		=300/0	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: rs739368; hg19: chr22-19939096;