Genetic Variant COMT:c.-1+51G>C (chr22-19961340-G-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+51G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 152,196 control chromosomes in the GnomAD database, including 17,701 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.48 ( 17686 hom., cov: 34)

Exomes 𝑓: 0.52 ( 15 hom. )

Consequence

COMT
NM_000754.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0930

Publications

37 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=-0.84).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
COMT	NM_000754.4 link	c.-1+51G>C	intron_variant	Intron 2 of 5	ENST00000361682.11	NP_000745.1
COMT	NM_001135161.2 link	c.-1+51G>C	intron_variant	Intron 2 of 5		NP_001128633.1
COMT	NM_001135162.2 link	c.-1+51G>C	intron_variant	Intron 2 of 5		NP_001128634.1
COMT	NM_001362828.2 link	c.-295+51G>C	intron_variant	Intron 2 of 5		NP_001349757.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COMT	ENST00000361682.11 link	c.-1+51G>C		intron_variant	Intron 2 of 5	1	NM_000754.4	ENSP00000354511.6

Frequencies

GnomAD3 genomes

AF:

0.479

AC:

72871

AN:

151978

Hom.:

17678

Cov.:

show subpopulations

Gnomad AFR

AF:

0.438

Gnomad AMI

AF:

0.664

Gnomad AMR

AF:

0.422

Gnomad ASJ

AF:

0.465

Gnomad EAS

AF:

0.268

Gnomad SAS

AF:

0.476

Gnomad FIN

AF:

0.551

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.522

Gnomad OTH

AF:

0.454

GnomAD4 exome

AF:

0.520

AC:

AN:

100

Hom.:

AF XY:

0.527

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.667

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.524

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<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:

0.479

AC:

72899

AN:

152096

Hom.:

17686

Cov.:

AF XY:

0.478

AC XY:

35553

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.437

AC:

18136

AN:

41480

American (AMR)

AF:

0.421

AC:

6453

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.465

AC:

1613

AN:

3472

East Asian (EAS)

AF:

0.269

AC:

1391

AN:

5174

South Asian (SAS)

AF:

0.475

AC:

2285

AN:

4806

European-Finnish (FIN)

AF:

0.551

AC:

5836

AN:

10584

Middle Eastern (MID)

AF:

0.476

AC:

140

AN:

294

European-Non Finnish (NFE)

AF:

0.522

AC:

35488

AN:

67956

Other (OTH)

AF:

0.451

AC:

951

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

2068

4136

6203

8271

10339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

656

1312

1968

2624

3280

<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:

0.370

Hom.:

1005

Bravo

AF:

0.465

Asia WGS

AF:

0.356

AC:

1238

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.2

(source)

DANN

Benign

0.43

PhyloP100

-0.093

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over