12-72004004-A-G

Position:

• chr12-72004004-A-G

Variant summary

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

The NM_173353.4(TPH2):​c.1068+9439A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 149,898 control chromosomes in the GnomAD database, including 20,617 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 0.51 (20617 hom., cov: 31)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.105

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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPH2	NM_173353.4	c.1068+9439A>G		intron_variant		ENST00000333850.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPH2	ENST00000333850.4	c.1068+9439A>G		intron_variant		1	NM_173353.4	P1

Frequencies

GnomAD3 genomes AF: 0.513 AC: 76859 AN: 149782 Hom.: 20609 Cov.: 31

Gnomad AFR AF: 0.415

Gnomad AMI AF: 0.653

Gnomad AMR AF: 0.543

Gnomad ASJ AF: 0.622

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.518

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.596

Gnomad NFE AF: 0.566

Gnomad OTH AF: 0.542

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

GnomAD4 genome AF: 0.513 AC: 76904 AN: 149898 Hom.: 20617 Cov.: 31 AF XY: 0.510 AC XY: 37299 AN XY: 73084

Gnomad4 AFR AF: 0.414

Gnomad4 AMR AF: 0.543

Gnomad4 ASJ AF: 0.622

Gnomad4 EAS AF: 0.468

Gnomad4 SAS AF: 0.519

Gnomad4 FIN AF: 0.481

Gnomad4 NFE AF: 0.566

Gnomad4 OTH AF: 0.542

Alfa AF: 0.530 Hom.: 2673

Bravo AF: 0.511

Asia WGS AF: 0.478 AC: 1666 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
DANN	Benign	0.61

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: rs1352250; hg19: chr12-72397784;