12-71938935-A-G

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.-52A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0727 in 1,467,598 control chromosomes in the GnomAD database, including 4,473 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.059 (367 hom., cov: 32)
  • Exomes 𝑓: 0.074 (4106 hom.)
• Consequence: TPH2 NM_173353.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.04

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 12-71938935-A-G is Benign according to our data. Variant chr12-71938935-A-G is described in ClinVar as [Benign]. Clinvar id is 310376.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPH2	NM_173353.4	c.-52A>G		5_prime_UTR_variant	1/11	ENST00000333850.4
TPH2	XR_001748575.2	n.91A>G		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPH2	ENST00000333850.4	c.-52A>G		5_prime_UTR_variant	1/11	1	NM_173353.4	P1
TPH2	ENST00000546576.1			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0590 AC: 8976 AN: 152128 Hom.: 365 Cov.: 32

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.0538

Gnomad AMR AF: 0.0739

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.0908

Gnomad FIN AF: 0.0764

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0713

Gnomad OTH AF: 0.0589

GnomAD4 exome AF: 0.0742 AC: 97635 AN: 1315352 Hom.: 4106 Cov.: 19 AF XY: 0.0752 AC XY: 49844 AN XY: 662400

Gnomad4 AFR exome AF: 0.0126

Gnomad4 AMR exome AF: 0.117

Gnomad4 ASJ exome AF: 0.0343

Gnomad4 EAS exome AF: 0.138

Gnomad4 SAS exome AF: 0.102

Gnomad4 FIN exome AF: 0.0723

Gnomad4 NFE exome AF: 0.0706

Gnomad4 OTH exome AF: 0.0720

GnomAD4 genome AF: 0.0590 AC: 8988 AN: 152246 Hom.: 367 Cov.: 32 AF XY: 0.0610 AC XY: 4538 AN XY: 74434

Gnomad4 AFR AF: 0.0141

Gnomad4 AMR AF: 0.0746

Gnomad4 ASJ AF: 0.0323

Gnomad4 EAS AF: 0.167

Gnomad4 SAS AF: 0.0909

Gnomad4 FIN AF: 0.0764

Gnomad4 NFE AF: 0.0713

Gnomad4 OTH AF: 0.0592

Alfa AF: 0.0607 Hom.: 41

Bravo AF: 0.0575

Asia WGS AF: 0.134 AC: 463 AN: 3478

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

Mar 06, 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	0.43
Dann	Benign	0.42

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: rs11178998; hg19: chr12-72332715; COSMIC: COSV61592099; COSMIC: COSV61592099;