12-71938935-A-G

Variant names:

• chr12-71938935-A-G
• rs11178998
• NM_173353.4:c.-52A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_173353.4(TPH2):​c.-52A>G variant causes a 5 prime UTR premature start codon gain 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_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.04
• Publications: 26 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 -20 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
TPH2	NM_173353.4	c.-52A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 11	ENST00000333850.4	NP_775489.2
TPH2	NM_173353.4	c.-52A>G		5_prime_UTR_variant	Exon 1 of 11	ENST00000333850.4	NP_775489.2
TPH2	XR_001748575.2	n.91A>G		non_coding_transcript_exon_variant	Exon 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPH2	ENST00000333850.4	c.-52A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 11	1	NM_173353.4	ENSP00000329093.3
TPH2	ENST00000333850.4	c.-52A>G		5_prime_UTR_variant	Exon 1 of 11	1	NM_173353.4	ENSP00000329093.3
TPH2	ENST00000546576.1	n.-42A>G		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

African (AFR) AF: 0.0126 AC: 383 AN: 30514

American (AMR) AF: 0.117 AC: 5227 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 865 AN: 25230

East Asian (EAS) AF: 0.138 AC: 5380 AN: 38988

South Asian (SAS) AF: 0.102 AC: 8491 AN: 83280

European-Finnish (FIN) AF: 0.0723 AC: 3760 AN: 52040

Middle Eastern (MID) AF: 0.0564 AC: 284 AN: 5038

European-Non Finnish (NFE) AF: 0.0706 AC: 69250 AN: 980250

Other (OTH) AF: 0.0720 AC: 3995 AN: 55474

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

African (AFR) AF: 0.0141 AC: 585 AN: 41558

American (AMR) AF: 0.0746 AC: 1142 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0323 AC: 112 AN: 3470

East Asian (EAS) AF: 0.167 AC: 863 AN: 5168

South Asian (SAS) AF: 0.0909 AC: 439 AN: 4830

European-Finnish (FIN) AF: 0.0764 AC: 810 AN: 10608

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0713 AC: 4847 AN: 67994

Other (OTH) AF: 0.0592 AC: 125 AN: 2112

Alfa AF: 0.0500 Hom.: 74

Bravo AF: 0.0575

Asia WGS AF: 0.134 AC: 463 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tryptophan 5-monooxygenase deficiency Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.43
DANN	Benign	0.42
PhyloP100		-2.0
PromoterAI		0.013	Neutral
Mutation Taster		=300/0	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: rs11178998; hg19: chr12-72332715; COSMIC: COSV61592099; COSMIC: COSV61592099;