Genetic Variant NM_173353.4:c.105+56_105+58delTCT (chr12-71939143-ATCT-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_173353.4(TPH2):c.105+56_105+58delTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0828 in 1,354,670 control chromosomes in the GnomAD database, including 5,886 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.12 ( 1287 hom., cov: 30)

Exomes 𝑓: 0.079 ( 4599 hom. )

Consequence

TPH2
NM_173353.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.331

Publications

1 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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPH2	NM_173353.4 link	c.105+56_105+58delTCT		intron_variant	Intron 1 of 10	ENST00000333850.4	NP_775489.2	Q8IWU9-1
TPH2	XR_001748575.2 link	n.247+56_247+58delTCT		intron_variant	Intron 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPH2	ENST00000333850.4 link	c.105+53_105+55delTCT		intron_variant	Intron 1 of 10	1	NM_173353.4	ENSP00000329093.3		Q8IWU9-1
TPH2	ENST00000546576.1 link	n.115+53_115+55delTCT		intron_variant	Intron 1 of 6	5

Frequencies

GnomAD3 genomes

AF:

0.116

AC:

17672

AN:

151982

Hom.:

1279

Cov.:

show subpopulations

Gnomad AFR

AF:

0.211

Gnomad AMI

AF:

0.0537

Gnomad AMR

AF:

0.0950

Gnomad ASJ

AF:

0.0357

Gnomad EAS

AF:

0.166

Gnomad SAS

AF:

0.113

Gnomad FIN

AF:

0.0758

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0720

Gnomad OTH

AF:

0.0968

GnomAD2 exomes

AF:

0.100

AC:

22249

AN:

221716

AF XY:

0.0964

show subpopulations

Gnomad AFR exome

AF:

0.214

Gnomad AMR exome

AF:

0.130

Gnomad ASJ exome

AF:

0.0365

Gnomad EAS exome

AF:

0.177

Gnomad FIN exome

AF:

0.0674

Gnomad NFE exome

AF:

0.0676

Gnomad OTH exome

AF:

0.0789

GnomAD4 exome

AF:

0.0785

AC:

94408

AN:

1202570

Hom.:

4599

AF XY:

0.0796

AC XY:

48609

AN XY:

610308

show subpopulations

African (AFR)

AF:

0.210

AC:

5919

AN:

28182

American (AMR)

AF:

0.125

AC:

5263

AN:

42100

Ashkenazi Jewish (ASJ)

AF:

0.0363

AC:

889

AN:

24482

East Asian (EAS)

AF:

0.135

AC:

5133

AN:

37916

South Asian (SAS)

AF:

0.120

AC:

9596

AN:

79810

European-Finnish (FIN)

AF:

0.0713

AC:

3281

AN:

46030

Middle Eastern (MID)

AF:

0.0687

AC:

364

AN:

5298

European-Non Finnish (NFE)

AF:

0.0672

AC:

59572

AN:

886890

Other (OTH)

AF:

0.0847

AC:

4391

AN:

51862

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

4766

9531

14297

19062

23828

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2098

4196

6294

8392

10490

<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:

0.117

AC:

17720

AN:

152100

Hom.:

1287

Cov.:

AF XY:

0.117

AC XY:

8678

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.211

AC:

8751

AN:

41462

American (AMR)

AF:

0.0957

AC:

1462

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0357

AC:

124

AN:

3470

East Asian (EAS)

AF:

0.167

AC:

861

AN:

5168

South Asian (SAS)

AF:

0.113

AC:

544

AN:

4824

European-Finnish (FIN)

AF:

0.0758

AC:

803

AN:

10592

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0720

AC:

4894

AN:

67994

Other (OTH)

AF:

0.100

AC:

211

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

770

1539

2309

3078

3848

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

200

400

600

800

1000

<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:

0.0885

Hom.:

135

Bravo

AF:

0.122

Asia WGS

AF:

0.165

AC:

571

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.33

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