chr12-72013178-T-C

Variant names:

• chr12-72013178-T-C
• rs10879352
• NM_173353.4:c.1069-9221T>C

Variant summary

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

The NM_173353.4(TPH2):​c.1069-9221T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.563 in 152,034 control chromosomes in the GnomAD database, including 24,458 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 0.56 (24458 hom., cov: 32)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08
• Publications: 4 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=-0.46).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.657 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.1069-9221T>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.1069-9221T>C		intron	N/A	ENSP00000329093.3	Q8IWU9-1

Frequencies

GnomAD3 genomes AF: 0.563 AC: 85580 AN: 151916 Hom.: 24429 Cov.: 32

Gnomad AFR AF: 0.474

Gnomad AMI AF: 0.693

Gnomad AMR AF: 0.628

Gnomad ASJ AF: 0.645

Gnomad EAS AF: 0.627

Gnomad SAS AF: 0.677

Gnomad FIN AF: 0.522

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.590

Gnomad OTH AF: 0.589

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

GnomAD4 genome AF: 0.563 AC: 85662 AN: 152034 Hom.: 24458 Cov.: 32 AF XY: 0.566 AC XY: 42069 AN XY: 74312

African (AFR) AF: 0.474 AC: 19662 AN: 41470

American (AMR) AF: 0.629 AC: 9601 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.645 AC: 2236 AN: 3468

East Asian (EAS) AF: 0.628 AC: 3245 AN: 5170

South Asian (SAS) AF: 0.676 AC: 3259 AN: 4822

European-Finnish (FIN) AF: 0.522 AC: 5510 AN: 10546

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

European-Non Finnish (NFE) AF: 0.590 AC: 40079 AN: 67964

Other (OTH) AF: 0.592 AC: 1251 AN: 2112

Alfa AF: 0.570 Hom.: 4595

Bravo AF: 0.564

Asia WGS AF: 0.670 AC: 2330 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Benign	0.68
PhyloP100		-1.1
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: rs10879352; hg19: chr12-72406958;