Genetic Variant TPH2:c.609-113C>T (chr12-71972406-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_173353.4(TPH2):c.609-113C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.553 in 967,504 control chromosomes in the GnomAD database, including 149,860 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 0.51 ( 20646 hom., cov: 33)

Exomes 𝑓: 0.56 ( 129214 hom. )

Consequence

TPH2
NM_173353.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.11

Publications

10 publications found

Variant links:

Genes affected

TPH2 (HGNC:20692): (tryptophan hydroxylase 2) This gene encodes a member of the pterin-dependent aromatic acid hydroxylase family. The encoded protein catalyzes the first and rate limiting step in the biosynthesis of serotonin, an important hormone and neurotransmitter. Mutations in this gene may be associated with psychiatric diseases such as bipolar affective disorder and major depression. [provided by RefSeq, Feb 2016]

TPH2 Gene-Disease associations (from GenCC):

attention deficit-hyperactivity disorder, susceptibility to, 7
Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

TPH2 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=-0.88).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173353.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPH2	NM_173353.4	MANE Select	c.609-113C>T		intron	N/A	NP_775489.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPH2	ENST00000333850.4	TSL:1 MANE Select	c.609-113C>T		intron	N/A	ENSP00000329093.3	Q8IWU9-1

Frequencies

GnomAD3 genomes

AF:

0.512

AC:

77785

AN:

151944

Hom.:

20634

Cov.:

show subpopulations

Gnomad AFR

AF:

0.370

Gnomad AMI

AF:

0.629

Gnomad AMR

AF:

0.529

Gnomad ASJ

AF:

0.626

Gnomad EAS

AF:

0.475

Gnomad SAS

AF:

0.526

Gnomad FIN

AF:

0.566

Gnomad MID

AF:

0.589

Gnomad NFE

AF:

0.579

Gnomad OTH

AF:

0.542

GnomAD4 exome

AF:

0.560

AC:

456830

AN:

815442

Hom.:

129214

AF XY:

0.561

AC XY:

241192

AN XY:

430040

show subpopulations

African (AFR)

AF:

0.370

AC:

7745

AN:

20952

American (AMR)

AF:

0.506

AC:

22068

AN:

43604

Ashkenazi Jewish (ASJ)

AF:

0.640

AC:

14110

AN:

22050

East Asian (EAS)

AF:

0.514

AC:

18863

AN:

36710

South Asian (SAS)

AF:

0.528

AC:

38327

AN:

72586

European-Finnish (FIN)

AF:

0.575

AC:

30257

AN:

52652

Middle Eastern (MID)

AF:

0.585

AC:

2085

AN:

3562

European-Non Finnish (NFE)

AF:

0.576

AC:

301799

AN:

524318

Other (OTH)

AF:

0.553

AC:

21576

AN:

39008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

10622

21244

31865

42487

53109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4898

9796

14694

19592

24490

<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:

0.512

AC:

77823

AN:

152062

Hom.:

20646

Cov.:

AF XY:

0.513

AC XY:

38097

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.370

AC:

15338

AN:

41448

American (AMR)

AF:

0.529

AC:

8079

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.626

AC:

2172

AN:

3468

East Asian (EAS)

AF:

0.475

AC:

2460

AN:

5176

South Asian (SAS)

AF:

0.528

AC:

2544

AN:

4820

European-Finnish (FIN)

AF:

0.566

AC:

5990

AN:

10580

Middle Eastern (MID)

AF:

0.588

AC:

173

AN:

294

European-Non Finnish (NFE)

AF:

0.579

AC:

39348

AN:

67974

Other (OTH)

AF:

0.542

AC:

1145

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1921

3842

5764

7685

9606

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

690

1380

2070

2760

3450

<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:

0.554

Hom.:

63991

Bravo

AF:

0.503

Asia WGS

AF:

0.489

AC:

1702

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.021

(source)

DANN

Benign

0.60

PhyloP100

-2.1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over