22-19963240-T-G

Variant names:

• chr22-19963240-T-G
• rs740601
• NM_000754.4:c.290-326T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000754.4(COMT):​c.290-326T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 502,898 control chromosomes in the GnomAD database, including 38,198 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 0.39 (11566 hom., cov: 32)
  • Exomes 𝑓: 0.38 (26632 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.138
• Publications: 17 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000754.4. 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.290-326T>G		intron	N/A	NP_000745.1	P21964-1
	COMT	NM_001135161.2		c.290-326T>G		intron	N/A	NP_001128633.1	P21964-1
	COMT	NM_001135162.2		c.290-326T>G		intron	N/A	NP_001128634.1	P21964-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	ENST00000361682.11	TSL:1 MANE Select	c.290-326T>G		intron	N/A	ENSP00000354511.6	P21964-1
	COMT	ENST00000406520.7	TSL:1	c.290-326T>G		intron	N/A	ENSP00000385150.3	P21964-1
	COMT	ENST00000449653.5	TSL:1	c.140-326T>G		intron	N/A	ENSP00000416778.1	P21964-2

Frequencies

GnomAD3 genomes AF: 0.390 AC: 59089 AN: 151694 Hom.: 11563 Cov.: 32

Gnomad AFR AF: 0.417

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.476

Gnomad EAS AF: 0.333

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.402

Gnomad OTH AF: 0.407

GnomAD4 exome AF: 0.384 AC: 134736 AN: 351086 Hom.: 26632 AF XY: 0.384 AC XY: 70104 AN XY: 182706

African (AFR) AF: 0.417 AC: 4528 AN: 10848

American (AMR) AF: 0.281 AC: 3654 AN: 13000

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 5121 AN: 11272

East Asian (EAS) AF: 0.316 AC: 7828 AN: 24772

South Asian (SAS) AF: 0.340 AC: 11227 AN: 32986

European-Finnish (FIN) AF: 0.326 AC: 7428 AN: 22818

Middle Eastern (MID) AF: 0.446 AC: 722 AN: 1618

European-Non Finnish (NFE) AF: 0.404 AC: 85936 AN: 212740

Other (OTH) AF: 0.394 AC: 8292 AN: 21032

GnomAD4 genome AF: 0.389 AC: 59123 AN: 151812 Hom.: 11566 Cov.: 32 AF XY: 0.384 AC XY: 28480 AN XY: 74186

African (AFR) AF: 0.417 AC: 17258 AN: 41376

American (AMR) AF: 0.334 AC: 5107 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.476 AC: 1649 AN: 3462

East Asian (EAS) AF: 0.332 AC: 1711 AN: 5154

South Asian (SAS) AF: 0.332 AC: 1600 AN: 4814

European-Finnish (FIN) AF: 0.311 AC: 3271 AN: 10528

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.402 AC: 27261 AN: 67886

Other (OTH) AF: 0.407 AC: 860 AN: 2114

Alfa AF: 0.397 Hom.: 3187

Bravo AF: 0.391

Asia WGS AF: 0.331 AC: 1153 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.4
DANN	Benign	0.57
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs740601; hg19: chr22-19950763;