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GeneBe

rs4680

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

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 0.44 in 151946 control chromosomes in the gnomAD Genomes database, including 15493 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 ( 15493 hom., cov: 33)
Exomes 𝑓: 0.46 ( 27151 hom. )

Consequence

COMT
NM_000754.4 missense

Scores

3
14

Clinical Significance

Benign criteria provided, single submitter B:6O:1

Conservation

PhyloP100: 0.146

Links

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 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_single_submitter, 1 stars. Variant chr22-19963748-G-A is described in Lovd as [Benign].
BA1
?
GnomAd 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
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
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:6Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:5
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, PreventionGenetics-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
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
9.8
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;