rs10506645

Variant names:

• chr12-71991720-C-T
• rs10506645
• NM_173353.4:c.942-2719C>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.942-2719C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 152,094 control chromosomes in the GnomAD database, including 4,930 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 0.25 (4930 hom., cov: 32)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.496
• Publications: 14 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]

TPH2 Gene-Disease associations (from GenCC):

• attention deficit-hyperactivity disorder, susceptibility to, 7

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173353.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPH2	NM_173353.4	MANE Select	c.942-2719C>T		intron	N/A	NP_775489.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPH2	ENST00000333850.4	TSL:1 MANE Select	c.942-2719C>T		intron	N/A	ENSP00000329093.3	Q8IWU9-1

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38470 AN: 151976 Hom.: 4924 Cov.: 32

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.246

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

GnomAD4 genome AF: 0.253 AC: 38491 AN: 152094 Hom.: 4930 Cov.: 32 AF XY: 0.251 AC XY: 18692 AN XY: 74352

African (AFR) AF: 0.279 AC: 11587 AN: 41470

American (AMR) AF: 0.244 AC: 3737 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 750 AN: 3470

East Asian (EAS) AF: 0.357 AC: 1846 AN: 5166

South Asian (SAS) AF: 0.217 AC: 1047 AN: 4820

European-Finnish (FIN) AF: 0.215 AC: 2275 AN: 10570

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16472 AN: 67994

Other (OTH) AF: 0.243 AC: 514 AN: 2112

Alfa AF: 0.245 Hom.: 14565

Bravo AF: 0.259

Asia WGS AF: 0.234 AC: 816 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.43
DANN	Benign	0.61
PhyloP100		-0.50
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: rs10506645; hg19: chr12-72385500;