rs4818

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000754.4(COMT):​c.408C>G​(p.Leu136Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 1,612,472 control chromosomes in the GnomAD database, including 116,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 8487 hom., cov: 33)
Exomes 𝑓: 0.38 ( 107780 hom. )

Consequence

COMT
NM_000754.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:2

Conservation

PhyloP100: 0.271
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.78).
BP6
Variant 22-19963684-C-G is Benign according to our data. Variant chr22-19963684-C-G is described in ClinVar as [Benign]. Clinvar id is 256786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-19963684-C-G is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=0.271 with no splicing effect.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.391 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COMTNM_000754.4 linkc.408C>G p.Leu136Leu synonymous_variant Exon 4 of 6 ENST00000361682.11 NP_000745.1 P21964-1A0A140VJG8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COMTENST00000361682.11 linkc.408C>G p.Leu136Leu synonymous_variant Exon 4 of 6 1 NM_000754.4 ENSP00000354511.6 P21964-1

Frequencies

GnomAD3 genomes
AF:
0.324
AC:
49164
AN:
151960
Hom.:
8492
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.206
Gnomad AMI
AF:
0.306
Gnomad AMR
AF:
0.304
Gnomad ASJ
AF:
0.471
Gnomad EAS
AF:
0.325
Gnomad SAS
AF:
0.311
Gnomad FIN
AF:
0.301
Gnomad MID
AF:
0.424
Gnomad NFE
AF:
0.395
Gnomad OTH
AF:
0.359
GnomAD2 exomes
AF:
0.338
AC:
84214
AN:
249446
AF XY:
0.346
show subpopulations
Gnomad AFR exome
AF:
0.197
Gnomad AMR exome
AF:
0.213
Gnomad ASJ exome
AF:
0.460
Gnomad EAS exome
AF:
0.323
Gnomad FIN exome
AF:
0.309
Gnomad NFE exome
AF:
0.395
Gnomad OTH exome
AF:
0.370
GnomAD4 exome
AF:
0.380
AC:
555409
AN:
1460394
Hom.:
107780
Cov.:
58
AF XY:
0.380
AC XY:
276355
AN XY:
726524
show subpopulations
Gnomad4 AFR exome
AF:
0.197
AC:
6599
AN:
33478
Gnomad4 AMR exome
AF:
0.222
AC:
9900
AN:
44690
Gnomad4 ASJ exome
AF:
0.460
AC:
12020
AN:
26134
Gnomad4 EAS exome
AF:
0.309
AC:
12249
AN:
39688
Gnomad4 SAS exome
AF:
0.320
AC:
27570
AN:
86254
Gnomad4 FIN exome
AF:
0.314
AC:
16367
AN:
52138
Gnomad4 NFE exome
AF:
0.401
AC:
445766
AN:
1111872
Gnomad4 Remaining exome
AF:
0.377
AC:
22774
AN:
60378
Heterozygous variant carriers
0
22809
45618
68427
91236
114045
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
13696
27392
41088
54784
68480
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.323
AC:
49172
AN:
152078
Hom.:
8487
Cov.:
33
AF XY:
0.320
AC XY:
23760
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.206
AC:
0.205891
AN:
0.205891
Gnomad4 AMR
AF:
0.304
AC:
0.303651
AN:
0.303651
Gnomad4 ASJ
AF:
0.471
AC:
0.470605
AN:
0.470605
Gnomad4 EAS
AF:
0.324
AC:
0.323804
AN:
0.323804
Gnomad4 SAS
AF:
0.311
AC:
0.310682
AN:
0.310682
Gnomad4 FIN
AF:
0.301
AC:
0.30068
AN:
0.30068
Gnomad4 NFE
AF:
0.395
AC:
0.395016
AN:
0.395016
Gnomad4 OTH
AF:
0.359
AC:
0.359242
AN:
0.359242
Heterozygous variant carriers
0
1730
3460
5190
6920
8650
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Genome Hom
Variant carriers
0
508
1016
1524
2032
2540
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.375
Hom.:
3482
Bravo
AF:
0.317
Asia WGS
AF:
0.311
AC:
1081
AN:
3478
EpiCase
AF:
0.416
EpiControl
AF:
0.409

ClinVar

Significance: Benign
Submissions summary: Benign:7Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
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

- -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
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

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

May 04, 2021
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19641441, 9323320, 30218069, 25766270) -

methamphetamine use disorder Other:1
Jan 16, 2023
Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology
Significance:Uncertain risk allele
Review Status:no assertion criteria provided
Collection Method:case-control

- -

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 v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.78
CADD
Benign
3.0
DANN
Benign
0.62
RBP_binding_hub_radar
1.0
RBP_regulation_power_radar
3.2
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

Publications

LitVar

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

Other links and lift over

dbSNP: rs4818; hg19: chr22-19951207; COSMIC: COSV52889002; COSMIC: COSV52889002; API