12-72004114-C-T

Variant names:

• chr12-72004114-C-T
• rs1352251
• NM_173353.4:c.1068+9549C>T

Variant summary

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

The NM_173353.4(TPH2):​c.1068+9549C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.549 in 144,922 control chromosomes in the GnomAD database, including 22,918 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 0.55 (22918 hom., cov: 31)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.49
• Publications: 2 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=-0.95).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.645 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.1068+9549C>T		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.1068+9549C>T		intron	N/A	ENSP00000329093.3	Q8IWU9-1

Frequencies

GnomAD3 genomes AF: 0.549 AC: 79550 AN: 144824 Hom.: 22901 Cov.: 31

Gnomad AFR AF: 0.432

Gnomad AMI AF: 0.697

Gnomad AMR AF: 0.622

Gnomad ASJ AF: 0.645

Gnomad EAS AF: 0.617

Gnomad SAS AF: 0.666

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.589

Gnomad OTH AF: 0.578

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

GnomAD4 genome AF: 0.549 AC: 79598 AN: 144922 Hom.: 22918 Cov.: 31 AF XY: 0.551 AC XY: 38777 AN XY: 70386

African (AFR) AF: 0.432 AC: 17174 AN: 39778

American (AMR) AF: 0.622 AC: 8647 AN: 13892

Ashkenazi Jewish (ASJ) AF: 0.645 AC: 2190 AN: 3396

East Asian (EAS) AF: 0.618 AC: 2645 AN: 4282

South Asian (SAS) AF: 0.666 AC: 2657 AN: 3990

European-Finnish (FIN) AF: 0.518 AC: 5207 AN: 10050

Middle Eastern (MID) AF: 0.633 AC: 181 AN: 286

European-Non Finnish (NFE) AF: 0.589 AC: 39112 AN: 66352

Other (OTH) AF: 0.581 AC: 1169 AN: 2012

Alfa AF: 0.566 Hom.: 9444

Bravo AF: 0.532

Asia WGS AF: 0.584 AC: 1945 AN: 3326

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.0050
DANN	Benign	0.39
PhyloP100		-4.5
Mutation Taster		=100/0	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: rs1352251; hg19: chr12-72397894;