rs4760816

Variant names:

• chr12-71978821-C-T
• rs4760816
• NM_173353.4:c.806-131C>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.806-131C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.568 in 1,099,092 control chromosomes in the GnomAD database, including 178,625 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 0.57 (25194 hom., cov: 33)
  • Exomes 𝑓: 0.57 (153431 hom.)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.834
• Publications: 16 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=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.579 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPH2	NM_173353.4	c.806-131C>T		intron_variant	Intron 6 of 10	ENST00000333850.4	NP_775489.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPH2	ENST00000333850.4	c.806-131C>T		intron_variant	Intron 6 of 10	1	NM_173353.4	ENSP00000329093.3

Frequencies

GnomAD3 genomes AF: 0.573 AC: 87120 AN: 151960 Hom.: 25173 Cov.: 33

Gnomad AFR AF: 0.586

Gnomad AMI AF: 0.632

Gnomad AMR AF: 0.550

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.565

Gnomad MID AF: 0.615

Gnomad NFE AF: 0.579

Gnomad OTH AF: 0.585

GnomAD4 exome AF: 0.567 AC: 537005 AN: 947014 Hom.: 153431 AF XY: 0.566 AC XY: 278881 AN XY: 492640

African (AFR) AF: 0.583 AC: 13514 AN: 23178

American (AMR) AF: 0.516 AC: 22107 AN: 42818

Ashkenazi Jewish (ASJ) AF: 0.641 AC: 14423 AN: 22506

East Asian (EAS) AF: 0.512 AC: 19066 AN: 37208

South Asian (SAS) AF: 0.528 AC: 39273 AN: 74410

European-Finnish (FIN) AF: 0.575 AC: 28106 AN: 48870

Middle Eastern (MID) AF: 0.582 AC: 2761 AN: 4740

European-Non Finnish (NFE) AF: 0.574 AC: 373288 AN: 650108

Other (OTH) AF: 0.567 AC: 24467 AN: 43176

GnomAD4 genome AF: 0.573 AC: 87183 AN: 152078 Hom.: 25194 Cov.: 33 AF XY: 0.571 AC XY: 42451 AN XY: 74338

African (AFR) AF: 0.586 AC: 24292 AN: 41480

American (AMR) AF: 0.550 AC: 8405 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 2175 AN: 3470

East Asian (EAS) AF: 0.472 AC: 2443 AN: 5172

South Asian (SAS) AF: 0.528 AC: 2545 AN: 4818

European-Finnish (FIN) AF: 0.565 AC: 5975 AN: 10576

Middle Eastern (MID) AF: 0.606 AC: 177 AN: 292

European-Non Finnish (NFE) AF: 0.579 AC: 39361 AN: 67964

Other (OTH) AF: 0.585 AC: 1236 AN: 2114

Alfa AF: 0.581 Hom.: 71564

Bravo AF: 0.574

Asia WGS AF: 0.499 AC: 1736 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	9.5
DANN	Benign	0.42
PhyloP100		0.83
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: rs4760816; hg19: chr12-72372601;