rs17110747

chr12-72032174-G-Achr12-72032174-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_173353.4(TPH2):c.*479G>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.128 in 174,672 control chromosomes in the GnomAD database, including 1,825 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1505 hom., cov: 32)
  • Exomes 𝑓: 0.16 (320 hom.)
• Consequence: TPH2 NM_173353.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.71

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-72032174-G-A is Benign according to our data. Variant chr12-72032174-G-A is described in ClinVar as [Benign]. Clinvar id is 310397.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPH2	NM_173353.4	c.*479G>A		3_prime_UTR_variant	11/11	ENST00000333850.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPH2	ENST00000333850.4	c.*479G>A		3_prime_UTR_variant	11/11	1	NM_173353.4	P1

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18816 AN: 151934 Hom.: 1508 Cov.: 32

Gnomad AFR AF: 0.0318

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.251

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.134

GnomAD4 exome AF: 0.155 AC: 3507 AN: 22620 Hom.: 320 Cov.: 0 AF XY: 0.161 AC XY: 1887 AN XY: 11698

Gnomad4 AFR exome AF: 0.0192

Gnomad4 AMR exome AF: 0.221

Gnomad4 ASJ exome AF: 0.189

Gnomad4 EAS exome AF: 0.249

Gnomad4 SAS exome AF: 0.176

Gnomad4 FIN exome AF: 0.139

Gnomad4 NFE exome AF: 0.130

Gnomad4 OTH exome AF: 0.146

GnomAD4 genome AF: 0.124 AC: 18796 AN: 152052 Hom.: 1505 Cov.: 32 AF XY: 0.127 AC XY: 9440 AN XY: 74312

Gnomad4 AFR AF: 0.0317

Gnomad4 AMR AF: 0.179

Gnomad4 ASJ AF: 0.184

Gnomad4 EAS AF: 0.250

Gnomad4 SAS AF: 0.177

Gnomad4 FIN AF: 0.183

Gnomad4 NFE AF: 0.140

Gnomad4 OTH AF: 0.133

Alfa AF: 0.141 Hom.: 709

Bravo AF: 0.120

Asia WGS AF: 0.194 AC: 672 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tryptophan 5-monooxygenase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	11
Dann	Benign	0.55

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: rs17110747; hg19: chr12-72425954;