12-71942989-C-T

Position:

• chr12-71942989-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173353.4(TPH2):​c.255+1256C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 151,934 control chromosomes in the GnomAD database, including 10,539 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 0.35 (10539 hom., cov: 31)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.26

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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.446 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPH2	NM_173353.4	c.255+1256C>T		intron_variant		ENST00000333850.4	NP_775489.2
TPH2	XR_001748575.2	n.397+1256C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPH2	ENST00000333850.4	c.255+1256C>T		intron_variant		1	NM_173353.4	ENSP00000329093.3
TPH2	ENST00000546576.1	n.265+1256C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.346 AC: 52591 AN: 151816 Hom.: 10538 Cov.: 31

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.475

Gnomad EAS AF: 0.289

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.398

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

GnomAD4 genome AF: 0.346 AC: 52601 AN: 151934 Hom.: 10539 Cov.: 31 AF XY: 0.344 AC XY: 25544 AN XY: 74242

Gnomad4 AFR AF: 0.145

Gnomad4 AMR AF: 0.360

Gnomad4 ASJ AF: 0.475

Gnomad4 EAS AF: 0.289

Gnomad4 SAS AF: 0.350

Gnomad4 FIN AF: 0.407

Gnomad4 NFE AF: 0.450

Gnomad4 OTH AF: 0.396

Alfa AF: 0.433 Hom.: 16433

Bravo AF: 0.337

Asia WGS AF: 0.327 AC: 1136 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.54
DANN	Benign	0.52

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: rs4565946; hg19: chr12-72336769;