dbSNP rs4818: COMT:p.Leu136Leu (chr22-19963684-C-G) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is The variant received -17 classification points (ACMG Germline Pathogenicity v2019): 0P and 17B. BA1BP4_StrongBP6_StrongBP7

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 cumulative frequency of 0.375 (AC=604,581) in the gnomAD database across 1,612,472 control chromosomes, including 116,267 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.4. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 8487 hom., cov: 33)

Exomes 𝑓: 0.38 ( 107780 hom. )

Consequence

COMT
NM_000754.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.271

Publications

370 publications found

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:

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]

MIR4761 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000754.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -17 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

BP7

Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.3999 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COMT	NM_000754.4	MANE Select	c.408C>G	p.Leu136Leu	synonymous	Exon 4 of 6	NP_000745.1	P21964-1
COMT	NM_001135161.2		c.408C>G	p.Leu136Leu	synonymous	Exon 4 of 6	NP_001128633.1	P21964-1
COMT	NM_001135162.2		c.408C>G	p.Leu136Leu	synonymous	Exon 4 of 6	NP_001128634.1	P21964-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COMT	ENST00000361682.11	TSL:1 MANE Select	c.408C>G	p.Leu136Leu	synonymous	Exon 4 of 6	ENSP00000354511.6	P21964-1
COMT	ENST00000406520.7	TSL:1	c.408C>G	p.Leu136Leu	synonymous	Exon 4 of 6	ENSP00000385150.3	P21964-1
COMT	ENST00000449653.5	TSL:1	c.258C>G	p.Leu86Leu	synonymous	Exon 2 of 4	ENSP00000416778.1	P21964-2

Frequencies

GnomAD3 genomes

AF:

0.324

AC:

49164

AN:

151960

Hom.:

8492

Cov.:

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.:

AF XY:

0.380

AC XY:

276355

AN XY:

726524

show subpopulations

African (AFR)

AF:

0.197

AC:

6599

AN:

33478

American (AMR)

AF:

0.222

AC:

9900

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.460

AC:

12020

AN:

26134

East Asian (EAS)

AF:

0.309

AC:

12249

AN:

39688

South Asian (SAS)

AF:

0.320

AC:

27570

AN:

86254

European-Finnish (FIN)

AF:

0.314

AC:

16367

AN:

52138

Middle Eastern (MID)

AF:

0.376

AC:

2164

AN:

5762

European-Non Finnish (NFE)

AF:

0.401

AC:

445766

AN:

1111872

Other (OTH)

AF:

0.377

AC:

22774

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

22809

45618

68427

91236

114045

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

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.:

AF XY:

0.320

AC XY:

23760

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.206

AC:

8542

AN:

41488

American (AMR)

AF:

0.304

AC:

4641

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.471

AC:

1633

AN:

3470

East Asian (EAS)

AF:

0.324

AC:

1665

AN:

5142

South Asian (SAS)

AF:

0.311

AC:

1495

AN:

4812

European-Finnish (FIN)

AF:

0.301

AC:

3186

AN:

10596

Middle Eastern (MID)

AF:

0.421

AC:

123

AN:

292

European-Non Finnish (NFE)

AF:

0.395

AC:

26850

AN:

67972

Other (OTH)

AF:

0.359

AC:

758

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1730

3460

5190

6920

8650

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

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

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.282

AC:

34526

AN:

122630

Turkish Variome

AF:

0.426

AC:

2845

AN:

6678

Hom.:

626

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.325

AC:

2908

AN:

8960

Hom.:

484

ABraOM SABE-WGS-1171

AF:

0.357

AC:

836

AN:

2342

Hom.:

155

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (2)

methamphetamine use disorder (1)

Tramadol response (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

3.0

(source)

DANN

Benign

0.62

PhyloP100

0.27

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

3.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over