22-19944145-A-G

Variant names:

• chr22-19944145-A-G
• rs1544325
• NM_000754.4:c.-92+2248A>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.-92+2248A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.624 in 151,900 control chromosomes in the GnomAD database, including 30,112 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 0.62 (30112 hom., cov: 31)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0760
• Publications: 49 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.719 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	NM_000754.4	MANE Select	c.-92+2248A>G		intron	N/A	NP_000745.1
	COMT	NM_001362828.2		c.-386+2248A>G		intron	N/A	NP_001349757.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	ENST00000361682.11	TSL:1 MANE Select	c.-92+2248A>G		intron	N/A	ENSP00000354511.6
	COMT	ENST00000678769.1		c.-92+2248A>G		intron	N/A	ENSP00000503289.1
	COMT	ENST00000428707.2	TSL:3	c.-92+2248A>G		intron	N/A	ENSP00000387695.2

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94686 AN: 151782 Hom.: 30063 Cov.: 31

Gnomad AFR AF: 0.726

Gnomad AMI AF: 0.491

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.712

Gnomad EAS AF: 0.710

Gnomad SAS AF: 0.638

Gnomad FIN AF: 0.479

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.563

Gnomad OTH AF: 0.659

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

GnomAD4 genome AF: 0.624 AC: 94796 AN: 151900 Hom.: 30112 Cov.: 31 AF XY: 0.624 AC XY: 46324 AN XY: 74204

African (AFR) AF: 0.726 AC: 30097 AN: 41438

American (AMR) AF: 0.669 AC: 10211 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.712 AC: 2471 AN: 3470

East Asian (EAS) AF: 0.709 AC: 3659 AN: 5158

South Asian (SAS) AF: 0.638 AC: 3058 AN: 4794

European-Finnish (FIN) AF: 0.479 AC: 5041 AN: 10530

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.563 AC: 38242 AN: 67932

Other (OTH) AF: 0.660 AC: 1392 AN: 2108

Alfa AF: 0.599 Hom.: 47559

Bravo AF: 0.641

Asia WGS AF: 0.686 AC: 2387 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	9.7
DANN	Benign	0.74
PhyloP100		0.076
Mutation Taster		=100/0	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: rs1544325; hg19: chr22-19931668;