rs45454096

chr22-19941996-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000754.4(COMT):c.-92+99G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0397 in 490,386 control chromosomes in the GnomAD database, including 466 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.042 (142 hom., cov: 32)
  • Exomes 𝑓: 0.039 (324 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.149

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 22-19941996-G-A is Benign according to our data. Variant chr22-19941996-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 678642.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.094 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMT	NM_000754.4	c.-92+99G>A		intron_variant		ENST00000361682.11
COMT	NM_001362828.2	c.-386+99G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMT	ENST00000361682.11	c.-92+99G>A		intron_variant		1	NM_000754.4	P2

Frequencies

GnomAD3 genomes AF: 0.0416 AC: 6320 AN: 152068 Hom.: 142 Cov.: 32

Gnomad AFR AF: 0.0421

Gnomad AMI AF: 0.0253

Gnomad AMR AF: 0.0533

Gnomad ASJ AF: 0.0292

Gnomad EAS AF: 0.0184

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.0197

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0399

Gnomad OTH AF: 0.0574

GnomAD4 exome AF: 0.0389 AC: 13163 AN: 338204 Hom.: 324 Cov.: 5 AF XY: 0.0410 AC XY: 7208 AN XY: 175762

Gnomad4 AFR exome AF: 0.0367

Gnomad4 AMR exome AF: 0.0533

Gnomad4 ASJ exome AF: 0.0287

Gnomad4 EAS exome AF: 0.0159

Gnomad4 SAS exome AF: 0.0886

Gnomad4 FIN exome AF: 0.0228

Gnomad4 NFE exome AF: 0.0382

Gnomad4 OTH exome AF: 0.0398

GnomAD4 genome AF: 0.0416 AC: 6326 AN: 152182 Hom.: 142 Cov.: 32 AF XY: 0.0411 AC XY: 3061 AN XY: 74410

Gnomad4 AFR AF: 0.0421

Gnomad4 AMR AF: 0.0533

Gnomad4 ASJ AF: 0.0292

Gnomad4 EAS AF: 0.0184

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.0197

Gnomad4 NFE AF: 0.0399

Gnomad4 OTH AF: 0.0573

Alfa AF: 0.0352 Hom.: 17

Bravo AF: 0.0430

Asia WGS AF: 0.0580 AC: 201 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	4.0
Dann	Benign	0.71

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: rs45454096; hg19: chr22-19929519;