dbSNP rs6269: COMT:c.1-98A>G (chr22-19962429-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001362828.2(COMT):c.-98A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.391 in 1,521,518 control chromosomes in the GnomAD database, including 117,448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 10887 hom., cov: 33)

Exomes 𝑓: 0.39 ( 106561 hom. )

Consequence

COMT
NM_001362828.2 5_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.47

Publications

249 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 22-19962429-A-G is Benign according to our data. Variant chr22-19962429-A-G is described in ClinVar as Benign. ClinVar VariationId is 1275060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001362828.2. 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.1-98A>G	intron	N/A	NP_000745.1	P21964-1
COMT	NM_001362828.2		c.-98A>G	5_prime_UTR	Exon 3 of 6	NP_001349757.1	P21964-1
COMT	NM_001135161.2		c.1-98A>G	intron	N/A	NP_001128633.1	P21964-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
COMT	ENST00000361682.11	TSL:1 MANE Select	c.1-98A>G	intron	N/A	ENSP00000354511.6	P21964-1
COMT	ENST00000406520.7	TSL:1	c.1-98A>G	intron	N/A	ENSP00000385150.3	P21964-1
COMT	ENST00000964896.1		c.-98A>G	5_prime_UTR	Exon 3 of 7	ENSP00000634955.1

Frequencies

GnomAD3 genomes

AF:

0.377

AC:

57285

AN:

152008

Hom.:

10884

Cov.:

show subpopulations

Gnomad AFR

AF:

0.375

Gnomad AMI

AF:

0.310

Gnomad AMR

AF:

0.331

Gnomad ASJ

AF:

0.475

Gnomad EAS

AF:

0.325

Gnomad SAS

AF:

0.330

Gnomad FIN

AF:

0.309

Gnomad MID

AF:

0.424

Gnomad NFE

AF:

0.401

Gnomad OTH

AF:

0.396

GnomAD4 exome

AF:

0.392

AC:

536868

AN:

1369392

Hom.:

106561

Cov.:

AF XY:

0.392

AC XY:

263406

AN XY:

672754

show subpopulations

African (AFR)

AF:

0.368

AC:

11627

AN:

31628

American (AMR)

AF:

0.244

AC:

8995

AN:

36810

Ashkenazi Jewish (ASJ)

AF:

0.462

AC:

11324

AN:

24486

East Asian (EAS)

AF:

0.295

AC:

10599

AN:

35886

South Asian (SAS)

AF:

0.339

AC:

26308

AN:

77622

European-Finnish (FIN)

AF:

0.325

AC:

11157

AN:

34330

Middle Eastern (MID)

AF:

0.435

AC:

1741

AN:

4004

European-Non Finnish (NFE)

AF:

0.405

AC:

432510

AN:

1067646

Other (OTH)

AF:

0.397

AC:

22607

AN:

56980

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

17619

35238

52858

70477

88096

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13672

27344

41016

54688

68360

<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:

0.377

AC:

57316

AN:

152126

Hom.:

10887

Cov.:

AF XY:

0.372

AC XY:

27645

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.375

AC:

15570

AN:

41494

American (AMR)

AF:

0.331

AC:

5056

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.475

AC:

1648

AN:

3470

East Asian (EAS)

AF:

0.324

AC:

1671

AN:

5160

South Asian (SAS)

AF:

0.330

AC:

1591

AN:

4824

European-Finnish (FIN)

AF:

0.309

AC:

3272

AN:

10598

Middle Eastern (MID)

AF:

0.425

AC:

125

AN:

294

European-Non Finnish (NFE)

AF:

0.401

AC:

27263

AN:

67968

Other (OTH)

AF:

0.396

AC:

838

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1865

3730

5596

7461

9326

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

570

1140

1710

2280

2850

<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:

0.383

Hom.:

21084

Bravo

AF:

0.378

Asia WGS

AF:

0.327

AC:

1141

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.68

(source)

DANN

Benign

0.39

PhyloP100

-2.5

PromoterAI

0.19

Neutral

(source)

Mutation Taster

=300/0

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

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