chr22-19965038-G-A

Position:

• chr22-19965038-G-A

Variant summary

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

The NM_000754.4(COMT):​c.615+739G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 163,790 control chromosomes in the GnomAD database, including 5,986 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 0.27 (5639 hom., cov: 33)
  • Exomes 𝑓: 0.22 (347 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.368

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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMT	NM_000754.4	c.615+739G>A		intron_variant		ENST00000361682.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMT	ENST00000361682.11	c.615+739G>A		intron_variant		1	NM_000754.4	P2

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40363 AN: 152074 Hom.: 5636 Cov.: 33

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.409

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.262

GnomAD4 exome AF: 0.220 AC: 2551 AN: 11596 Hom.: 347 Cov.: 0 AF XY: 0.222 AC XY: 1328 AN XY: 5992

Gnomad4 AFR exome AF: 0.155

Gnomad4 AMR exome AF: 0.178

Gnomad4 ASJ exome AF: 0.235

Gnomad4 EAS exome AF: 0.0746

Gnomad4 SAS exome AF: 0.156

Gnomad4 FIN exome AF: 0.192

Gnomad4 NFE exome AF: 0.270

Gnomad4 OTH exome AF: 0.251

GnomAD4 genome AF: 0.265 AC: 40370 AN: 152194 Hom.: 5639 Cov.: 33 AF XY: 0.261 AC XY: 19384 AN XY: 74394

Gnomad4 AFR AF: 0.219

Gnomad4 AMR AF: 0.213

Gnomad4 ASJ AF: 0.318

Gnomad4 EAS AF: 0.139

Gnomad4 SAS AF: 0.197

Gnomad4 FIN AF: 0.250

Gnomad4 NFE AF: 0.318

Gnomad4 OTH AF: 0.261

Alfa AF: 0.295 Hom.: 5314

Bravo AF: 0.260

Asia WGS AF: 0.177 AC: 616 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.47

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: rs165774; hg19: chr22-19952561;