rs6269

Positions:

• chr22-19962429-A-G
• chr22-19962429-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000754.4(COMT):​c.1-98A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.391 in 1,521,518 control chromosomes in the GnomAD database, including 117,448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (10887 hom., cov: 33)
  • Exomes 𝑓: 0.39 (106561 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.47

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 22-19962429-A-G is Benign according to our data. Variant chr22-19962429-A-G is described in ClinVar as [Benign]. Clinvar id is 1275060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	Protein	UniProt
COMT	NM_000754.4	c.1-98A>G		intron_variant		ENST00000361682.11	NP_000745.1
COMT	NM_001362828.2	c.-98A>G		5_prime_UTR_variant	3/6		NP_001349757.1
COMT	NM_001135161.2	c.1-98A>G		intron_variant			NP_001128633.1
COMT	NM_001135162.2	c.1-98A>G		intron_variant			NP_001128634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COMT	ENST00000361682.11	c.1-98A>G		intron_variant		1	NM_000754.4	ENSP00000354511	P2

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57285 AN: 152008 Hom.: 10884 Cov.: 33

Gnomad AFR AF: 0.375

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.475

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.396

GnomAD4 exome AF: 0.392 AC: 536868 AN: 1369392 Hom.: 106561 Cov.: 30 AF XY: 0.392 AC XY: 263406 AN XY: 672754

Gnomad4 AFR exome AF: 0.368

Gnomad4 AMR exome AF: 0.244

Gnomad4 ASJ exome AF: 0.462

Gnomad4 EAS exome AF: 0.295

Gnomad4 SAS exome AF: 0.339

Gnomad4 FIN exome AF: 0.325

Gnomad4 NFE exome AF: 0.405

Gnomad4 OTH exome AF: 0.397

GnomAD4 genome AF: 0.377 AC: 57316 AN: 152126 Hom.: 10887 Cov.: 33 AF XY: 0.372 AC XY: 27645 AN XY: 74372

Gnomad4 AFR AF: 0.375

Gnomad4 AMR AF: 0.331

Gnomad4 ASJ AF: 0.475

Gnomad4 EAS AF: 0.324

Gnomad4 SAS AF: 0.330

Gnomad4 FIN AF: 0.309

Gnomad4 NFE AF: 0.401

Gnomad4 OTH AF: 0.396

Alfa AF: 0.376 Hom.: 3423

Bravo AF: 0.378

Asia WGS AF: 0.327 AC: 1141 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.68
DANN	Benign	0.39

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: rs6269; hg19: chr22-19949952; COSMIC: COSV52891062; COSMIC: COSV52891062;