rs3810595

Positions:

• chr22-19962121-G-C

Variant summary

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

The NM_000754.4(COMT):​c.1-406G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 296,138 control chromosomes in the GnomAD database, including 21,536 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 0.38 (10869 hom., cov: 33)
  • Exomes 𝑓: 0.37 (10667 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.54

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMT	NM_000754.4	c.1-406G>C		intron_variant		ENST00000361682.11
COMT	NM_001135161.2	c.1-406G>C		intron_variant
COMT	NM_001135162.2	c.1-406G>C		intron_variant
COMT	NM_001362828.2	c.-294-112G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMT	ENST00000361682.11	c.1-406G>C		intron_variant		1	NM_000754.4	P2

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57257 AN: 151970 Hom.: 10865 Cov.: 33

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.475

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.423

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.395

GnomAD4 exome AF: 0.374 AC: 53893 AN: 144048 Hom.: 10667 AF XY: 0.374 AC XY: 28542 AN XY: 76410

Gnomad4 AFR exome AF: 0.364

Gnomad4 AMR exome AF: 0.276

Gnomad4 ASJ exome AF: 0.449

Gnomad4 EAS exome AF: 0.322

Gnomad4 SAS exome AF: 0.340

Gnomad4 FIN exome AF: 0.332

Gnomad4 NFE exome AF: 0.397

Gnomad4 OTH exome AF: 0.381

GnomAD4 genome AF: 0.377 AC: 57289 AN: 152090 Hom.: 10869 Cov.: 33 AF XY: 0.372 AC XY: 27650 AN XY: 74360

Gnomad4 AFR AF: 0.375

Gnomad4 AMR AF: 0.330

Gnomad4 ASJ AF: 0.475

Gnomad4 EAS AF: 0.324

Gnomad4 SAS AF: 0.329

Gnomad4 FIN AF: 0.309

Gnomad4 NFE AF: 0.401

Gnomad4 OTH AF: 0.396

Alfa AF: 0.380 Hom.: 1353

Bravo AF: 0.377

Asia WGS AF: 0.327 AC: 1140 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.96
DANN	Benign	0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs3810595; hg19: chr22-19949644;