12-71999134-G-A

Variant names:

• chr12-71999134-G-A
• rs12229394
• NM_173353.4:c.1068+4569G>A

Variant summary

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

The NM_173353.4(TPH2):​c.1068+4569G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 152,048 control chromosomes in the GnomAD database, including 6,915 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 0.30 (6915 hom., cov: 33)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.862
• Publications: 8 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.472 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPH2	NM_173353.4	c.1068+4569G>A		intron_variant	Intron 8 of 10	ENST00000333850.4	NP_775489.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPH2	ENST00000333850.4	c.1068+4569G>A		intron_variant	Intron 8 of 10	1	NM_173353.4	ENSP00000329093.3

Frequencies

GnomAD3 genomes AF: 0.296 AC: 45042 AN: 151932 Hom.: 6910 Cov.: 33

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.489

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.289

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

GnomAD4 genome AF: 0.296 AC: 45071 AN: 152048 Hom.: 6915 Cov.: 33 AF XY: 0.302 AC XY: 22447 AN XY: 74330

African (AFR) AF: 0.293 AC: 12133 AN: 41466

American (AMR) AF: 0.336 AC: 5131 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 849 AN: 3466

East Asian (EAS) AF: 0.488 AC: 2523 AN: 5168

South Asian (SAS) AF: 0.385 AC: 1861 AN: 4828

European-Finnish (FIN) AF: 0.313 AC: 3303 AN: 10558

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.270 AC: 18322 AN: 67968

Other (OTH) AF: 0.291 AC: 613 AN: 2110

Alfa AF: 0.280 Hom.: 3513

Bravo AF: 0.297

Asia WGS AF: 0.422 AC: 1468 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.71
PhyloP100		0.86
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12229394; hg19: chr12-72392914;