12-72012752-T-C

Variant names:

• chr12-72012752-T-C
• rs3903502
• NM_173353.4:c.1069-9647T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173353.4(TPH2):​c.1069-9647T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.573 in 151,996 control chromosomes in the GnomAD database, including 25,141 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 0.57 (25141 hom., cov: 32)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.309
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.656 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.1069-9647T>C		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.1069-9647T>C		intron	N/A	ENSP00000329093.3	Q8IWU9-1

Frequencies

GnomAD3 genomes AF: 0.573 AC: 86954 AN: 151878 Hom.: 25110 Cov.: 32

Gnomad AFR AF: 0.506

Gnomad AMI AF: 0.693

Gnomad AMR AF: 0.630

Gnomad ASJ AF: 0.644

Gnomad EAS AF: 0.625

Gnomad SAS AF: 0.676

Gnomad FIN AF: 0.521

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.590

Gnomad OTH AF: 0.595

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.573 AC: 87043 AN: 151996 Hom.: 25141 Cov.: 32 AF XY: 0.575 AC XY: 42704 AN XY: 74300

African (AFR) AF: 0.507 AC: 21003 AN: 41452

American (AMR) AF: 0.631 AC: 9641 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.644 AC: 2234 AN: 3468

East Asian (EAS) AF: 0.626 AC: 3219 AN: 5144

South Asian (SAS) AF: 0.676 AC: 3257 AN: 4820

European-Finnish (FIN) AF: 0.521 AC: 5511 AN: 10570

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.590 AC: 40094 AN: 67946

Other (OTH) AF: 0.598 AC: 1266 AN: 2116

Alfa AF: 0.573 Hom.: 4540

Bravo AF: 0.575

Asia WGS AF: 0.671 AC: 2335 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.4
DANN	Benign	0.76
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3903502; hg19: chr12-72406532;