12-71942989-C-T

Variant names:

• chr12-71942989-C-T
• rs4565946
• NM_173353.4:c.255+1256C>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.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
• Publications: 35 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]

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
TPH2	NM_173353.4	c.255+1256C>T		intron_variant	Intron 2 of 10	ENST00000333850.4	NP_775489.2
TPH2	XR_001748575.2	n.397+1256C>T		intron_variant	Intron 2 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPH2	ENST00000333850.4	c.255+1256C>T		intron_variant	Intron 2 of 10	1	NM_173353.4	ENSP00000329093.3
TPH2	ENST00000546576.1	n.265+1256C>T		intron_variant	Intron 2 of 6	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

African (AFR) AF: 0.145 AC: 6013 AN: 41444

American (AMR) AF: 0.360 AC: 5497 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 1648 AN: 3468

East Asian (EAS) AF: 0.289 AC: 1491 AN: 5162

South Asian (SAS) AF: 0.350 AC: 1682 AN: 4810

European-Finnish (FIN) AF: 0.407 AC: 4281 AN: 10518

Middle Eastern (MID) AF: 0.462 AC: 135 AN: 292

European-Non Finnish (NFE) AF: 0.450 AC: 30578 AN: 67946

Other (OTH) AF: 0.396 AC: 837 AN: 2112

Alfa AF: 0.416 Hom.: 44918

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
PhyloP100		-1.3
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: rs4565946; hg19: chr12-72336769; COSMIC: COSV107377800;