rs11178998

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-71938935-A-G
• chr12-71938935-A-C

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]

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 -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 VariationId 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.

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.-52A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_775489.2
	TPH2	NM_173353.4	MANE Select	c.-52A>G		5_prime_UTR	Exon 1 of 11	NP_775489.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPH2	ENST00000333850.4	TSL:1 MANE Select	c.-52A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000329093.3	Q8IWU9-1
	TPH2	ENST00000333850.4	TSL:1 MANE Select	c.-52A>G		5_prime_UTR	Exon 1 of 11	ENSP00000329093.3	Q8IWU9-1
	TPH2	ENST00000546576.1	TSL:5	n.-42A>G		upstream_gene	N/A

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Tryptophan 5-monooxygenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

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;