rs4633

Variant names:

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.186C>T(p.His62His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.492 in 1,613,292 control chromosomes in the GnomAD database, including 198,896 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.45 ( 15737 hom., cov: 34)

Exomes 𝑓: 0.50 ( 183159 hom. )

Consequence

COMT
NM_000754.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.83

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]

COMT links:

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=-0.69).

BP6

Variant 22-19962712-C-T is Benign according to our data. Variant chr22-19962712-C-T is described in ClinVar as [Benign]. Clinvar id is 256785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-19962712-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.83 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4 link	c.186C>T	p.His62His	synonymous_variant	Exon 3 of 6	ENST00000361682.11	NP_000745.1	P21964-1A0A140VJG8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COMT	ENST00000361682.11 link	c.186C>T	p.His62His	synonymous_variant	Exon 3 of 6	1	NM_000754.4	ENSP00000354511.6		P21964-1

Frequencies

GnomAD3 genomes

AF:

0.446

AC:

67786

AN:

152012

Hom.:

15738

Cov.:

show subpopulations

Gnomad AFR

AF:

0.331

Gnomad AMI

AF:

0.664

Gnomad AMR

AF:

0.405

Gnomad ASJ

AF:

0.460

Gnomad EAS

AF:

0.269

Gnomad SAS

AF:

0.457

Gnomad FIN

AF:

0.551

Gnomad MID

AF:

0.465

Gnomad NFE

AF:

0.518

Gnomad OTH

AF:

0.425

GnomAD2 exomes

AF:

0.463

AC:

115901

AN:

250082

AF XY:

0.467

show subpopulations

Gnomad AFR exome

AF:

0.332

Gnomad AMR exome

AF:

0.405

Gnomad ASJ exome

AF:

0.470

Gnomad EAS exome

AF:

0.269

Gnomad FIN exome

AF:

0.545

Gnomad NFE exome

AF:

0.519

Gnomad OTH exome

AF:

0.475

GnomAD4 exome

AF:

0.497

AC:

726681

AN:

1461162

Hom.:

183159

Cov.:

AF XY:

0.497

AC XY:

361149

AN XY:

726878

show subpopulations

Gnomad4 AFR exome

AF:

0.328

AC:

10985

AN:

33478

Gnomad4 AMR exome

AF:

0.409

AC:

18280

AN:

44678

Gnomad4 ASJ exome

AF:

0.470

AC:

12279

AN:

26130

Gnomad4 EAS exome

AF:

0.279

AC:

11062

AN:

39690

Gnomad4 SAS exome

AF:

0.457

AC:

39419

AN:

86248

Gnomad4 FIN exome

AF:

0.546

AC:

28947

AN:

52984

Gnomad4 NFE exome

AF:

0.517

AC:

574537

AN:

1111814

Gnomad4 Remaining exome

AF:

0.468

AC:

28246

AN:

60376

Heterozygous variant carriers

21761

43522

65283

87044

108805

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

16364

32728

49092

65456

81820

<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:

0.446

AC:

67797

AN:

152130

Hom.:

15737

Cov.:

AF XY:

0.445

AC XY:

33124

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.330

AC:

0.330377

AN:

0.330377

Gnomad4 AMR

AF:

0.405

AC:

0.40484

AN:

0.40484

Gnomad4 ASJ

AF:

0.460

AC:

0.459919

AN:

0.459919

Gnomad4 EAS

AF:

0.270

AC:

0.269722

AN:

0.269722

Gnomad4 SAS

AF:

0.456

AC:

0.455846

AN:

0.455846

Gnomad4 FIN

AF:

0.551

AC:

0.550576

AN:

0.550576

Gnomad4 NFE

AF:

0.518

AC:

0.518467

AN:

0.518467

Gnomad4 OTH

AF:

0.423

AC:

0.422895

AN:

0.422895

Heterozygous variant carriers

1908

3816

5725

7633

9541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

624

1248

1872

2496

3120

<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:

0.488

Hom.:

51863

Bravo

AF:

0.427

Asia WGS

AF:

0.347

AC:

1206

AN:

3478

EpiCase

AF:

0.499

EpiControl

AF:

0.504

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

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: 21486747) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

-0.69

CADD

Benign

0.72

DANN

Benign

0.92

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over