22-19963748-G-A

Variant names:

• chr22-19963748-G-A
• rs4680
• NM_000754.4:c.472G>A

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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:8 O:1
• Conservation: PhyloP100: 0.146
• Publications: 3701 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 17591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000754.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	NM_000754.4	MANE Select	c.472G>A	p.Val158Met	missense	Exon 4 of 6	NP_000745.1
	COMT	NM_001135161.2		c.472G>A	p.Val158Met	missense	Exon 4 of 6	NP_001128633.1
	COMT	NM_001135162.2		c.472G>A	p.Val158Met	missense	Exon 4 of 6	NP_001128634.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	ENST00000361682.11	TSL:1 MANE Select	c.472G>A	p.Val158Met	missense	Exon 4 of 6	ENSP00000354511.6
	COMT	ENST00000406520.7	TSL:1	c.472G>A	p.Val158Met	missense	Exon 4 of 6	ENSP00000385150.3
	COMT	ENST00000449653.5	TSL:1	c.322G>A	p.Val108Met	missense	Exon 2 of 4	ENSP00000416778.1

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

GnomAD2 exomes AF: 0.461 AC: 114049 AN: 247346 AF XY: 0.465

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 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

African (AFR) AF: 0.301 AC: 10088 AN: 33480

American (AMR) AF: 0.408 AC: 18227 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.460 AC: 12019 AN: 26116

East Asian (EAS) AF: 0.286 AC: 11337 AN: 39680

South Asian (SAS) AF: 0.448 AC: 38648 AN: 86224

European-Finnish (FIN) AF: 0.550 AC: 27915 AN: 50782

Middle Eastern (MID) AF: 0.505 AC: 2915 AN: 5768

European-Non Finnish (NFE) AF: 0.516 AC: 573929 AN: 1111588

Other (OTH) AF: 0.465 AC: 28093 AN: 60354

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

African (AFR) AF: 0.310 AC: 12853 AN: 41484

American (AMR) AF: 0.404 AC: 6184 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.453 AC: 1571 AN: 3466

East Asian (EAS) AF: 0.274 AC: 1414 AN: 5152

South Asian (SAS) AF: 0.445 AC: 2147 AN: 4822

European-Finnish (FIN) AF: 0.553 AC: 5854 AN: 10592

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.518 AC: 35191 AN: 67942

Other (OTH) AF: 0.418 AC: 883 AN: 2110

Alfa AF: 0.484 Hom.: 75209

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:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Schizophrenia Benign:1

Center for Forensic Mental Health, Chiba University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: case-control

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

CATECHOL-O-METHYLTRANSFERASE POLYMORPHISM Benign:1

Jan 01, 2011

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

Tramadol response Other:1

Apr 28, 2018

Bruce Budowle Laboratory, University of North Texas Health Science Center

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

T:M1 = postmortem ratio or tramadol to O-desmethyltramadol; t-MP = model-based clustered metabolizer phenotype inferred from T:M1

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.000066	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.15
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.66	N
REVEL	Benign	0.25
Sift	Benign	0.22	T
Sift4G	Uncertain	0.029	D
Polyphen		0.016	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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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