rs1386486

Variant names:

• chr12-72018440-A-G
• rs1386486
• NM_173353.4:c.1069-3959A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173353.4(TPH2):​c.1069-3959A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.527 in 152,066 control chromosomes in the GnomAD database, including 22,462 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 0.53 (22462 hom., cov: 32)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.48
• Publications: 10 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPH2	NM_173353.4	c.1069-3959A>G		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.1069-3959A>G		intron_variant	Intron 8 of 10	1	NM_173353.4	ENSP00000329093.3

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80164 AN: 151948 Hom.: 22454 Cov.: 32

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.665

Gnomad AMR AF: 0.548

Gnomad ASJ AF: 0.609

Gnomad EAS AF: 0.477

Gnomad SAS AF: 0.518

Gnomad FIN AF: 0.510

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.638

Gnomad OTH AF: 0.560

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

GnomAD4 genome AF: 0.527 AC: 80206 AN: 152066 Hom.: 22462 Cov.: 32 AF XY: 0.523 AC XY: 38874 AN XY: 74328

African (AFR) AF: 0.338 AC: 14022 AN: 41484

American (AMR) AF: 0.548 AC: 8372 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.609 AC: 2113 AN: 3470

East Asian (EAS) AF: 0.478 AC: 2468 AN: 5162

South Asian (SAS) AF: 0.519 AC: 2506 AN: 4824

European-Finnish (FIN) AF: 0.510 AC: 5385 AN: 10560

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.638 AC: 43378 AN: 67976

Other (OTH) AF: 0.558 AC: 1177 AN: 2110

Alfa AF: 0.614 Hom.: 12710

Bravo AF: 0.522

Asia WGS AF: 0.478 AC: 1663 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0050
DANN	Benign	0.34
PhyloP100		-2.5
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: rs1386486; hg19: chr12-72412220;