NM_173353.4:c.608+9108T>C

Variant names:

• chr12-71958763-T-C
• rs1386494
• NM_173353.4:c.608+9108T>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.608+9108T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.828 in 152,172 control chromosomes in the GnomAD database, including 52,398 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 0.83 (52398 hom., cov: 32)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.03
• Publications: 49 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.922 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPH2	NM_173353.4	MANE Select	c.608+9108T>C		intron	N/A	NP_775489.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPH2	ENST00000333850.4	TSL:1 MANE Select	c.608+9108T>C		intron	N/A	ENSP00000329093.3
	TPH2	ENST00000546576.1	TSL:5	n.619-2790T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.828 AC: 125916 AN: 152054 Hom.: 52364 Cov.: 32

Gnomad AFR AF: 0.752

Gnomad AMI AF: 0.915

Gnomad AMR AF: 0.873

Gnomad ASJ AF: 0.870

Gnomad EAS AF: 0.945

Gnomad SAS AF: 0.900

Gnomad FIN AF: 0.824

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.847

Gnomad OTH AF: 0.843

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

GnomAD4 genome AF: 0.828 AC: 125999 AN: 152172 Hom.: 52398 Cov.: 32 AF XY: 0.830 AC XY: 61776 AN XY: 74406

African (AFR) AF: 0.751 AC: 31160 AN: 41474

American (AMR) AF: 0.873 AC: 13350 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.870 AC: 3019 AN: 3470

East Asian (EAS) AF: 0.944 AC: 4893 AN: 5182

South Asian (SAS) AF: 0.901 AC: 4344 AN: 4820

European-Finnish (FIN) AF: 0.824 AC: 8737 AN: 10600

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.847 AC: 57629 AN: 68020

Other (OTH) AF: 0.844 AC: 1785 AN: 2114

Alfa AF: 0.840 Hom.: 87155

Bravo AF: 0.828

Asia WGS AF: 0.907 AC: 3152 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	10
DANN	Benign	0.77
PhyloP100		1.0
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: rs1386494; hg19: chr12-72352543;