Genetic Variant NM_173353.4:c.541-81C>T (chr12-71949507-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.541-81C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0369 in 1,154,528 control chromosomes in the GnomAD database, including 1,449 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 0.043 ( 206 hom., cov: 32)

Exomes 𝑓: 0.036 ( 1243 hom. )

Consequence

TPH2
NM_173353.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.135

Publications

6 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:

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=-0.57).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPH2	NM_173353.4 link	c.541-81C>T		intron_variant	Intron 4 of 10	ENST00000333850.4	NP_775489.2	Q8IWU9-1
TPH2	XR_001748575.2 link	n.683-81C>T		intron_variant	Intron 4 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPH2	ENST00000333850.4 link	c.541-81C>T		intron_variant	Intron 4 of 10	1	NM_173353.4	ENSP00000329093.3		Q8IWU9-1
TPH2	ENST00000546576.1 link	n.551-81C>T		intron_variant	Intron 4 of 6	5

Frequencies

GnomAD3 genomes

AF:

0.0432

AC:

6566

AN:

152144

Hom.:

205

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0637

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0440

Gnomad ASJ

AF:

0.0248

Gnomad EAS

AF:

0.118

Gnomad SAS

AF:

0.130

Gnomad FIN

AF:

0.0143

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0244

Gnomad OTH

AF:

0.0450

GnomAD4 exome

AF:

0.0360

AC:

36041

AN:

1002266

Hom.:

1243

AF XY:

0.0387

AC XY:

20070

AN XY:

518914

show subpopulations

African (AFR)

AF:

0.0654

AC:

1584

AN:

24208

American (AMR)

AF:

0.0534

AC:

2291

AN:

42884

Ashkenazi Jewish (ASJ)

AF:

0.0232

AC:

532

AN:

22882

East Asian (EAS)

AF:

0.0913

AC:

3359

AN:

36774

South Asian (SAS)

AF:

0.116

AC:

8784

AN:

75952

European-Finnish (FIN)

AF:

0.0118

AC:

602

AN:

51118

Middle Eastern (MID)

AF:

0.0460

AC:

210

AN:

4570

European-Non Finnish (NFE)

AF:

0.0241

AC:

16814

AN:

699060

Other (OTH)

AF:

0.0416

AC:

1865

AN:

44818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1736

3472

5209

6945

8681

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

644

1288

1932

2576

3220

<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:

0.0432

AC:

6577

AN:

152262

Hom.:

206

Cov.:

AF XY:

0.0445

AC XY:

3311

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0638

AC:

2653

AN:

41552

American (AMR)

AF:

0.0439

AC:

671

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0248

AC:

AN:

3470

East Asian (EAS)

AF:

0.117

AC:

606

AN:

5174

South Asian (SAS)

AF:

0.129

AC:

622

AN:

4826

European-Finnish (FIN)

AF:

0.0143

AC:

152

AN:

10614

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0244

AC:

1657

AN:

68012

Other (OTH)

AF:

0.0488

AC:

103

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

317

635

952

1270

1587

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

246

328

410

<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:

0.0330

Hom.:

278

Bravo

AF:

0.0450

Asia WGS

AF:

0.167

AC:

581

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

7.4

(source)

DANN

Benign

0.59

PhyloP100

0.14

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