rs4680

chr22-19963748-G-A

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.472G>A(p.Val158Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 1,610,688 control chromosomes in the GnomAD database, including 197,380 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15489 hom., cov: 33)
  • Exomes 𝑓: 0.50 (181891 hom.)
• Consequence: COMT NM_000754.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.146

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]

MIR4761 (HGNC:41591): (microRNA 4761) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.567385E-5).
• BP6: Variant 22-19963748-G-A is Benign according to our data. Variant chr22-19963748-G-A is described in ClinVar as [Benign]. Clinvar id is 17591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-19963748-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMT	NM_000754.4	c.472G>A	p.Val158Met	missense_variant	4/6	ENST00000361682.11
MIR4761	NR_039918.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMT	ENST00000361682.11	c.472G>A	p.Val158Met	missense_variant	4/6	1	NM_000754.4	P2
MIR4761	ENST00000585066.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66834 AN: 151946 Hom.: 15493 Cov.: 33

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.453

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.446

Gnomad FIN AF: 0.553

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.420

GnomAD3 exomes AF: 0.461 AC: 114049 AN: 247346 Hom.: 27151 AF XY: 0.465 AC XY: 62409 AN XY: 134140

Gnomad AFR exome AF: 0.311

Gnomad AMR exome AF: 0.405

Gnomad ASJ exome AF: 0.461

Gnomad EAS exome AF: 0.272

Gnomad SAS exome AF: 0.440

Gnomad FIN exome AF: 0.553

Gnomad NFE exome AF: 0.520

Gnomad OTH exome AF: 0.474

GnomAD4 exome AF: 0.496 AC: 723171 AN: 1458624 Hom.: 181891 Cov.: 65 AF XY: 0.495 AC XY: 359427 AN XY: 725604

Gnomad4 AFR exome AF: 0.301

Gnomad4 AMR exome AF: 0.408

Gnomad4 ASJ exome AF: 0.460

Gnomad4 EAS exome AF: 0.286

Gnomad4 SAS exome AF: 0.448

Gnomad4 FIN exome AF: 0.550

Gnomad4 NFE exome AF: 0.516

Gnomad4 OTH exome AF: 0.465

GnomAD4 genome AF: 0.440 AC: 66839 AN: 152064 Hom.: 15489 Cov.: 33 AF XY: 0.440 AC XY: 32667 AN XY: 74322

Gnomad4 AFR AF: 0.310

Gnomad4 AMR AF: 0.404

Gnomad4 ASJ AF: 0.453

Gnomad4 EAS AF: 0.274

Gnomad4 SAS AF: 0.445

Gnomad4 FIN AF: 0.553

Gnomad4 NFE AF: 0.518

Gnomad4 OTH AF: 0.418

Alfa AF: 0.487 Hom.: 36118

Bravo AF: 0.420

TwinsUK AF: 0.502 AC: 1860

ALSPAC AF: 0.512 AC: 1974

ESP6500AA AF: 0.315 AC: 1387

ESP6500EA AF: 0.522 AC: 4485

ExAC AF: 0.462 AC: 56093

Asia WGS AF: 0.344 AC: 1197 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Schizophrenia Benign:1

Benign, criteria provided, single submitter

case-control

Center for Forensic Mental Health, Chiba University

-

- -

CATECHOL-O-METHYLTRANSFERASE POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jan 01, 2011

- -

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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T;.;T;T;T;T;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.25	N
MetaRNN	Benign	0.000066	T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.0	M;.;M;M;.;M;.
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.66	N;N;N;.;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.22	T;T;T;.;T;T;T
Sift4G	Uncertain	0.029	D;D;D;D;D;D;T
Polyphen		0.016	B;P;B;B;.;B;.
Vest4		0.073
MPC		0.36
ClinPred		0.0047	T
GERP RS		-0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.46

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: rs4680; hg19: chr22-19951271; COSMIC: COSV52889256; COSMIC: COSV52889256;