rs11569716

Positions:

• chr22-19962224-T-C

Variant summary

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

The NM_000754.4(COMT):​c.1-303T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 472,890 control chromosomes in the GnomAD database, including 300 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.033 (225 hom., cov: 33)
  • Exomes 𝑓: 0.0086 (75 hom.)
• Consequence: COMT NM_000754.4 intron
• Scores: Splicing: ADA: 0.00003774
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -0.808

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COMT	NM_000754.4	c.1-303T>C		intron_variant		ENST00000361682.11	NP_000745.1
COMT	NM_001135161.2	c.1-303T>C		intron_variant			NP_001128633.1
COMT	NM_001135162.2	c.1-303T>C		intron_variant			NP_001128634.1
COMT	NM_001362828.2	c.-294-9T>C		intron_variant			NP_001349757.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COMT	ENST00000361682.11	c.1-303T>C		intron_variant		1	NM_000754.4	ENSP00000354511.6

Frequencies

GnomAD3 genomes AF: 0.0327 AC: 4974 AN: 152000 Hom.: 225 Cov.: 33

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0191

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00354

Gnomad OTH AF: 0.0277

GnomAD4 exome AF: 0.00856 AC: 2747 AN: 320772 Hom.: 75 Cov.: 2 AF XY: 0.00871 AC XY: 1461 AN XY: 167784

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.0114

Gnomad4 ASJ exome AF: 0.00212

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0172

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00353

Gnomad4 OTH exome AF: 0.0120

GnomAD4 genome AF: 0.0328 AC: 4994 AN: 152118 Hom.: 225 Cov.: 33 AF XY: 0.0320 AC XY: 2382 AN XY: 74366

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.0156

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0195

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00355

Gnomad4 OTH AF: 0.0274

Alfa AF: 0.0215 Hom.: 19

Bravo AF: 0.0371

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Tramadol response Other:1

drug response, no assertion criteria provided

research

Bruce Budowle Laboratory, University of North Texas Health Science Center

Apr 28, 2018

- T:M1 = postmortem ratio or tramadol to O-desmethyltramadol; t-MP = model-based clustered metabolizer phenotype inferred from T:M1

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.6
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.0020
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: rs11569716; hg19: chr22-19949747;