rs781518671

Variant names:

• chr12-71939023-T-C
• rs781518671
• NM_173353.4:c.37T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-71939023-T-C
• chr12-71939023-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_173353.4(TPH2):​c.37T>C​(p.Trp13Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: TPH2 NM_173353.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.46

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.764

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPH2	NM_173353.4	c.37T>C	p.Trp13Arg	missense_variant	Exon 1 of 11	ENST00000333850.4	NP_775489.2
TPH2	XR_001748575.2	n.179T>C		non_coding_transcript_exon_variant	Exon 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPH2	ENST00000333850.4	c.37T>C	p.Trp13Arg	missense_variant	Exon 1 of 11	1	NM_173353.4	ENSP00000329093.3
TPH2	ENST00000546576.1	n.47T>C		non_coding_transcript_exon_variant	Exon 1 of 7	5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.070	T
Eigen	Benign	0.015
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.0	M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.85	N
REVEL	Uncertain	0.61
Sift	Benign	0.054	T
Sift4G	Benign	0.39	T
Polyphen		0.0030	B
Vest4		0.84
MutPred		0.48		Gain of disorder (P = 3e-04);
MVP		0.82
MPC		1.5
ClinPred		0.92	D
GERP RS		5.5
Varity_R		0.40
gMVP		0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs781518671; hg19: chr12-72332803;