Genetic Variant NM_000754.4:c.615+310C>T (chr22-19964609-C-T) – 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.615+310C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 602,952 control chromosomes in the GnomAD database, including 15,749 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 0.22 ( 3828 hom., cov: 33)

Exomes 𝑓: 0.23 ( 11921 hom. )

Consequence

COMT
NM_000754.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.472

Publications

71 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=-0.87).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4 link	c.615+310C>T		intron_variant	Intron 5 of 5	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.615+310C>T		intron_variant	Intron 5 of 5	1	NM_000754.4	ENSP00000354511.6		P21964-1

Frequencies

GnomAD3 genomes

AF:

0.219

AC:

33372

AN:

152042

Hom.:

3832

Cov.:

show subpopulations

Gnomad AFR

AF:

0.195

Gnomad AMI

AF:

0.161

Gnomad AMR

AF:

0.195

Gnomad ASJ

AF:

0.246

Gnomad EAS

AF:

0.310

Gnomad SAS

AF:

0.152

Gnomad FIN

AF:

0.200

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.240

Gnomad OTH

AF:

0.238

GnomAD4 exome

AF:

0.225

AC:

101573

AN:

450792

Hom.:

11921

Cov.:

AF XY:

0.221

AC XY:

52683

AN XY:

237878

show subpopulations

African (AFR)

AF:

0.198

AC:

2484

AN:

12522

American (AMR)

AF:

0.168

AC:

3234

AN:

19282

Ashkenazi Jewish (ASJ)

AF:

0.230

AC:

3157

AN:

13756

East Asian (EAS)

AF:

0.287

AC:

8927

AN:

31128

South Asian (SAS)

AF:

0.147

AC:

6756

AN:

45990

European-Finnish (FIN)

AF:

0.196

AC:

5788

AN:

29458

Middle Eastern (MID)

AF:

0.226

AC:

447

AN:

1976

European-Non Finnish (NFE)

AF:

0.240

AC:

64805

AN:

270580

Other (OTH)

AF:

0.229

AC:

5975

AN:

26100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

4119

8238

12356

16475

20594

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

368

736

1104

1472

1840

<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:

0.219

AC:

33377

AN:

152160

Hom.:

3828

Cov.:

AF XY:

0.219

AC XY:

16282

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.195

AC:

8082

AN:

41518

American (AMR)

AF:

0.195

AC:

2978

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.246

AC:

853

AN:

3472

East Asian (EAS)

AF:

0.309

AC:

1600

AN:

5170

South Asian (SAS)

AF:

0.152

AC:

735

AN:

4828

European-Finnish (FIN)

AF:

0.200

AC:

2122

AN:

10590

Middle Eastern (MID)

AF:

0.228

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.240

AC:

16295

AN:

67970

Other (OTH)

AF:

0.236

AC:

498

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1384

2769

4153

5538

6922

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

366

732

1098

1464

1830

<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:

0.230

Hom.:

14613

Bravo

AF:

0.220

Asia WGS

AF:

0.223

AC:

777

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

4.3

(source)

DANN

Benign

0.43

PhyloP100

-0.47

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

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