12-71954918-G-T

Variant names:

• chr12-71954918-G-T
• rs1843809
• NM_173353.4:c.608+5263G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_173353.4(TPH2):​c.608+5263G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.774 in 151,878 control chromosomes in the GnomAD database, including 46,823 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 0.77 (46823 hom., cov: 30)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.620
• Publications: 46 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.922 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.608+5263G>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.608+5263G>T		intron	N/A	ENSP00000329093.3	Q8IWU9-1
	TPH2	ENST00000546576.1	TSL:5	n.618+5263G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.775 AC: 117543 AN: 151758 Hom.: 46798 Cov.: 30

Gnomad AFR AF: 0.566

Gnomad AMI AF: 0.916

Gnomad AMR AF: 0.853

Gnomad ASJ AF: 0.870

Gnomad EAS AF: 0.944

Gnomad SAS AF: 0.892

Gnomad FIN AF: 0.825

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.846

Gnomad OTH AF: 0.805

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

GnomAD4 genome AF: 0.774 AC: 117612 AN: 151878 Hom.: 46823 Cov.: 30 AF XY: 0.779 AC XY: 57843 AN XY: 74258

African (AFR) AF: 0.566 AC: 23379 AN: 41288

American (AMR) AF: 0.853 AC: 13042 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.870 AC: 3018 AN: 3470

East Asian (EAS) AF: 0.944 AC: 4885 AN: 5176

South Asian (SAS) AF: 0.893 AC: 4299 AN: 4814

European-Finnish (FIN) AF: 0.825 AC: 8702 AN: 10548

Middle Eastern (MID) AF: 0.827 AC: 243 AN: 294

European-Non Finnish (NFE) AF: 0.846 AC: 57504 AN: 67980

Other (OTH) AF: 0.807 AC: 1706 AN: 2114

Alfa AF: 0.824 Hom.: 157486

Bravo AF: 0.766

Asia WGS AF: 0.897 AC: 3116 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Benign	0.75
PhyloP100		0.62
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: rs1843809; hg19: chr12-72348698;