12-72012752-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPH2	NM_173353.4	c.1069-9647T>C		intron_variant		ENST00000333850.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPH2	ENST00000333850.4	c.1069-9647T>C		intron_variant		1	NM_173353.4	P1

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

Gnomad4 AFR AF: 0.507

Gnomad4 AMR AF: 0.631

Gnomad4 ASJ AF: 0.644

Gnomad4 EAS AF: 0.626

Gnomad4 SAS AF: 0.676

Gnomad4 FIN AF: 0.521

Gnomad4 NFE AF: 0.590

Gnomad4 OTH AF: 0.598

Alfa AF: 0.574 Hom.: 4415

Bravo AF: 0.575

Asia WGS AF: 0.671 AC: 2335 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	5.4
Dann	Benign	0.76

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

LitVar

Other links and lift over

dbSNP: rs3903502; hg19: chr12-72406532;