12-71968598-G-C

Variant names:

• chr12-71968598-G-C
• rs1386491
• NM_173353.4:c.609-3921G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173353.4(TPH2):​c.609-3921G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 152,188 control chromosomes in the GnomAD database, including 3,209 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 0.19 (3209 hom., cov: 33)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0770
• Publications: 3 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.33 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.609-3921G>C		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.609-3921G>C		intron	N/A	ENSP00000329093.3	Q8IWU9-1

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28373 AN: 152070 Hom.: 3213 Cov.: 33

Gnomad AFR AF: 0.0541

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.343

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.194

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

GnomAD4 genome AF: 0.186 AC: 28361 AN: 152188 Hom.: 3209 Cov.: 33 AF XY: 0.187 AC XY: 13895 AN XY: 74430

African (AFR) AF: 0.0540 AC: 2243 AN: 41560

American (AMR) AF: 0.219 AC: 3344 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 759 AN: 3470

East Asian (EAS) AF: 0.343 AC: 1763 AN: 5142

South Asian (SAS) AF: 0.204 AC: 984 AN: 4826

European-Finnish (FIN) AF: 0.215 AC: 2274 AN: 10588

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.240 AC: 16333 AN: 67996

Other (OTH) AF: 0.192 AC: 405 AN: 2114

Alfa AF: 0.107 Hom.: 177

Bravo AF: 0.183

Asia WGS AF: 0.215 AC: 746 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.72
DANN	Benign	0.45
PhyloP100		-0.077
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1386491; hg19: chr12-72362378; COSMIC: COSV61594342; COSMIC: COSV61594342;