chr12-71946293-G-T

Variant names:

• chr12-71946293-G-T
• rs2129575
• NM_173353.4:c.540+1607G>T

Variant summary

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

The NM_173353.4(TPH2):​c.540+1607G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 152,032 control chromosomes in the GnomAD database, including 5,446 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 0.26 (5446 hom., cov: 32)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.431
• Publications: 19 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.512 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.540+1607G>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.540+1607G>T		intron	N/A	ENSP00000329093.3	Q8IWU9-1
	TPH2	ENST00000546576.1	TSL:5	n.550+1607G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39026 AN: 151914 Hom.: 5438 Cov.: 32

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.267

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.529

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.257

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

GnomAD4 genome AF: 0.257 AC: 39065 AN: 152032 Hom.: 5446 Cov.: 32 AF XY: 0.260 AC XY: 19289 AN XY: 74326

African (AFR) AF: 0.238 AC: 9892 AN: 41476

American (AMR) AF: 0.306 AC: 4673 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 888 AN: 3470

East Asian (EAS) AF: 0.528 AC: 2727 AN: 5164

South Asian (SAS) AF: 0.327 AC: 1576 AN: 4816

European-Finnish (FIN) AF: 0.205 AC: 2166 AN: 10570

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.240 AC: 16286 AN: 67962

Other (OTH) AF: 0.259 AC: 546 AN: 2110

Alfa AF: 0.250 Hom.: 3064

Bravo AF: 0.264

Asia WGS AF: 0.423 AC: 1470 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Benign	0.50
PhyloP100		0.43
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: rs2129575; hg19: chr12-72340073;