dbSNP rs11569716: COMT:c.1-303T>C (chr22-19962224-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000754.4(COMT):c.1-303T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 472,890 control chromosomes in the GnomAD database, including 300 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

Frequency

Genomes: 𝑓 0.033 ( 225 hom., cov: 33)

Exomes 𝑓: 0.0086 ( 75 hom. )

Consequence

COMT
NM_000754.4 intron

Scores

Splicing: ADA: 0.00003774

Clinical Significance

drug response no assertion criteria provided O:1

Conservation

PhyloP100: -0.808

Publications

4 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 Gene-Disease associations (from GenCC):

paroxysmal dyskinesia
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

COMT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
COMT	NM_000754.4	MANE Select	c.1-303T>C	intron	N/A	NP_000745.1	P21964-1
COMT	NM_001135161.2		c.1-303T>C	intron	N/A	NP_001128633.1	P21964-1
COMT	NM_001135162.2		c.1-303T>C	intron	N/A	NP_001128634.1	P21964-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
COMT	ENST00000361682.11	TSL:1 MANE Select	c.1-303T>C	intron	N/A	ENSP00000354511.6	P21964-1
COMT	ENST00000406520.7	TSL:1	c.1-303T>C	intron	N/A	ENSP00000385150.3	P21964-1
COMT	ENST00000678255.1		c.-303T>C	5_prime_UTR	Exon 3 of 6	ENSP00000504402.1	P21964-1

Frequencies

GnomAD3 genomes

AF:

0.0327

AC:

4974

AN:

152000

Hom.:

225

Cov.:

show subpopulations

Gnomad AFR

AF:

0.105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0156

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0191

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00354

Gnomad OTH

AF:

0.0277

GnomAD4 exome

AF:

0.00856

AC:

2747

AN:

320772

Hom.:

Cov.:

AF XY:

0.00871

AC XY:

1461

AN XY:

167784

show subpopulations

African (AFR)

AF:

0.103

AC:

1000

AN:

9718

American (AMR)

AF:

0.0114

AC:

161

AN:

14118

Ashkenazi Jewish (ASJ)

AF:

0.00212

AC:

AN:

9886

East Asian (EAS)

AF:

0.00

AC:

AN:

20482

South Asian (SAS)

AF:

0.0172

AC:

647

AN:

37578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19800

Middle Eastern (MID)

AF:

0.0191

AC:

AN:

1410

European-Non Finnish (NFE)

AF:

0.00353

AC:

667

AN:

189058

Other (OTH)

AF:

0.0120

AC:

224

AN:

18722

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

124

247

371

494

618

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.0328

AC:

4994

AN:

152118

Hom.:

225

Cov.:

AF XY:

0.0320

AC XY:

2382

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.105

AC:

4343

AN:

41480

American (AMR)

AF:

0.0156

AC:

239

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.0195

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00355

AC:

241

AN:

67976

Other (OTH)

AF:

0.0274

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

219

437

656

874

1093

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<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:

0.0215

Hom.:

Bravo

AF:

0.0371

Asia WGS

AF:

0.00895

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:drug response

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Tramadol response (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

2.6

(source)

DANN

Benign

0.53

PhyloP100

-0.81

PromoterAI

-0.016

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000038

dbscSNV1_RF

Benign

0.0020

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over