rs4760820

Variant names:

• chr12-72003216-C-G
• rs4760820
• NM_173353.4:c.1068+8651C>G

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+8651C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 151,900 control chromosomes in the GnomAD database, including 8,201 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 0.29 (8201 hom., cov: 31)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.19
• Publications: 14 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=-0.75).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.405 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPH2	NM_173353.4	c.1068+8651C>G		intron_variant	Intron 8 of 10	ENST00000333850.4	NP_775489.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPH2	ENST00000333850.4	c.1068+8651C>G		intron_variant	Intron 8 of 10	1	NM_173353.4	ENSP00000329093.3

Frequencies

GnomAD3 genomes AF: 0.293 AC: 44439 AN: 151784 Hom.: 8199 Cov.: 31

Gnomad AFR AF: 0.0917

Gnomad AMI AF: 0.454

Gnomad AMR AF: 0.297

Gnomad ASJ AF: 0.483

Gnomad EAS AF: 0.0964

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.339

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

GnomAD4 genome AF: 0.293 AC: 44440 AN: 151900 Hom.: 8201 Cov.: 31 AF XY: 0.290 AC XY: 21524 AN XY: 74226

African (AFR) AF: 0.0917 AC: 3803 AN: 41468

American (AMR) AF: 0.297 AC: 4532 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.483 AC: 1675 AN: 3466

East Asian (EAS) AF: 0.0967 AC: 499 AN: 5162

South Asian (SAS) AF: 0.189 AC: 904 AN: 4794

European-Finnish (FIN) AF: 0.384 AC: 4034 AN: 10510

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.409 AC: 27755 AN: 67920

Other (OTH) AF: 0.334 AC: 706 AN: 2112

Alfa AF: 0.358 Hom.: 1596

Bravo AF: 0.278

Asia WGS AF: 0.147 AC: 512 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	16
DANN	Benign	0.60
PhyloP100		1.2
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: rs4760820; hg19: chr12-72396996;