12-72011279-T-C

Variant names:

• chr12-72011279-T-C
• rs1487276
• NM_173353.4:c.1069-11120T>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.1069-11120T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.809 in 152,194 control chromosomes in the GnomAD database, including 49,975 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 0.81 (49975 hom., cov: 33)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.104
• Publications: 8 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=-0.63).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.907 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.1069-11120T>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.1069-11120T>C		intron	N/A	ENSP00000329093.3	Q8IWU9-1

Frequencies

GnomAD3 genomes AF: 0.809 AC: 123018 AN: 152076 Hom.: 49932 Cov.: 33

Gnomad AFR AF: 0.748

Gnomad AMI AF: 0.914

Gnomad AMR AF: 0.863

Gnomad ASJ AF: 0.837

Gnomad EAS AF: 0.929

Gnomad SAS AF: 0.874

Gnomad FIN AF: 0.781

Gnomad MID AF: 0.825

Gnomad NFE AF: 0.821

Gnomad OTH AF: 0.822

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

GnomAD4 genome AF: 0.809 AC: 123118 AN: 152194 Hom.: 49975 Cov.: 33 AF XY: 0.811 AC XY: 60363 AN XY: 74398

African (AFR) AF: 0.748 AC: 31057 AN: 41506

American (AMR) AF: 0.863 AC: 13190 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.837 AC: 2906 AN: 3470

East Asian (EAS) AF: 0.929 AC: 4808 AN: 5178

South Asian (SAS) AF: 0.874 AC: 4217 AN: 4824

European-Finnish (FIN) AF: 0.781 AC: 8278 AN: 10600

Middle Eastern (MID) AF: 0.825 AC: 241 AN: 292

European-Non Finnish (NFE) AF: 0.821 AC: 55846 AN: 68014

Other (OTH) AF: 0.825 AC: 1743 AN: 2114

Alfa AF: 0.823 Hom.: 86190

Bravo AF: 0.813

Asia WGS AF: 0.883 AC: 3072 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.8
DANN	Benign	0.54
PhyloP100		0.10
Mutation Taster		=98/2	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: rs1487276; hg19: chr12-72405059;