rs74745580

Variant names:

• chr22-19962643-C-T
• rs74745580
• ENST00000449653.5:c.-34C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-19962643-C-T
• chr22-19962643-C-A
• chr22-19962643-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007310.3(COMT):​c.-34C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,604,504 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (37 hom.)
• Consequence: COMT NM_007310.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.825
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 22-19962643-C-T is Benign according to our data. Variant chr22-19962643-C-T is described in ClinVar as Benign. ClinVar VariationId is 717115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0024 (365/152258) while in subpopulation SAS AF = 0.0193 (93/4814). AF 95% confidence interval is 0.0161. There are 1 homozygotes in GnomAd4. There are 204 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 365 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007310.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	NM_000754.4	MANE Select	c.117C>T	p.Asn39Asn	synonymous	Exon 3 of 6	NP_000745.1	P21964-1
	COMT	NM_007310.3		c.-34C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	NP_009294.1	P21964-2
	COMT	NM_001135161.2		c.117C>T	p.Asn39Asn	synonymous	Exon 3 of 6	NP_001128633.1	P21964-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	ENST00000449653.5	TSL:1	c.-34C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000416778.1	P21964-2
	COMT	ENST00000361682.11	TSL:1 MANE Select	c.117C>T	p.Asn39Asn	synonymous	Exon 3 of 6	ENSP00000354511.6	P21964-1
	COMT	ENST00000406520.7	TSL:1	c.117C>T	p.Asn39Asn	synonymous	Exon 3 of 6	ENSP00000385150.3	P21964-1

Frequencies

GnomAD3 genomes AF: 0.00241 AC: 366 AN: 152142 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.00444

Gnomad SAS AF: 0.0195

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00427 AC: 992 AN: 232378 AF XY: 0.00533

Gnomad AFR exome AF: 0.000212

Gnomad AMR exome AF: 0.000580

Gnomad ASJ exome AF: 0.0274

Gnomad EAS exome AF: 0.00380

Gnomad FIN exome AF: 0.0000518

Gnomad NFE exome AF: 0.000920

Gnomad OTH exome AF: 0.00386

GnomAD4 exome AF: 0.00232 AC: 3370 AN: 1452246 Hom.: 37 Cov.: 52 AF XY: 0.00285 AC XY: 2056 AN XY: 721742

African (AFR) AF: 0.000180 AC: 6 AN: 33248

American (AMR) AF: 0.00113 AC: 49 AN: 43344

Ashkenazi Jewish (ASJ) AF: 0.0270 AC: 701 AN: 25964

East Asian (EAS) AF: 0.00435 AC: 170 AN: 39050

South Asian (SAS) AF: 0.0179 AC: 1525 AN: 85060

European-Finnish (FIN) AF: 0.0000196 AC: 1 AN: 51130

Middle Eastern (MID) AF: 0.00713 AC: 41 AN: 5750

European-Non Finnish (NFE) AF: 0.000584 AC: 648 AN: 1108744

Other (OTH) AF: 0.00382 AC: 229 AN: 59956

GnomAD4 genome AF: 0.00240 AC: 365 AN: 152258 Hom.: 1 Cov.: 33 AF XY: 0.00274 AC XY: 204 AN XY: 74426

African (AFR) AF: 0.000313 AC: 13 AN: 41556

American (AMR) AF: 0.00399 AC: 61 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0285 AC: 99 AN: 3472

East Asian (EAS) AF: 0.00445 AC: 23 AN: 5170

South Asian (SAS) AF: 0.0193 AC: 93 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00100 AC: 68 AN: 68008

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00270 Hom.: 2

Bravo AF: 0.00241

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	2.3
DANN	Benign	0.64
PhyloP100		-0.82
PromoterAI		0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs74745580; hg19: chr22-19950166;