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GeneBe

rs4680

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 12/19 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

Scores

3
14

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 0.146
Variant links:
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]

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ACMG classification

Classification made for transcript

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
COMTNM_000754.4 linkuse as main transcriptc.472G>A p.Val158Met missense_variant 4/6 ENST00000361682.11
MIR4761NR_039918.1 linkuse as main transcript upstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COMTENST00000361682.11 linkuse as main transcriptc.472G>A p.Val158Met missense_variant 4/61 NM_000754.4 P2P21964-1
MIR4761ENST00000585066.1 linkuse as main transcript upstream_gene_variant

Frequencies

GnomAD3 genomes
AF:
0.440
AC:
66834
AN:
151946
Hom.:
15493
Cov.:
33
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Schizophrenia Benign:1
Benign, criteria provided, single submittercase-controlCenter for Forensic Mental Health, Chiba University-- -
CATECHOL-O-METHYLTRANSFERASE POLYMORPHISM Benign:1
Benign, no assertion criteria providedliterature onlyOMIMJan 01, 2011- -
Tramadol response Other:1
drug response, no assertion criteria providedresearchBruce Budowle Laboratory, University of North Texas Health Science CenterApr 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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