12-71940903-G-T

Variant names:

• chr12-71940903-G-T
• rs4641527
• NM_173353.4:c.106-681G>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.106-681G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 151,830 control chromosomes in the GnomAD database, including 9,209 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 0.33 (9209 hom., cov: 32)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.73
• 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPH2	NM_173353.4	c.106-681G>T		intron_variant	Intron 1 of 10	ENST00000333850.4	NP_775489.2
TPH2	XR_001748575.2	n.248-681G>T		intron_variant	Intron 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPH2	ENST00000333850.4	c.106-681G>T		intron_variant	Intron 1 of 10	1	NM_173353.4	ENSP00000329093.3
TPH2	ENST00000546576.1	n.116-681G>T		intron_variant	Intron 1 of 6	5

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49357 AN: 151710 Hom.: 9186 Cov.: 32

Gnomad AFR AF: 0.492

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.536

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.245

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.311

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

GnomAD4 genome AF: 0.326 AC: 49424 AN: 151830 Hom.: 9209 Cov.: 32 AF XY: 0.323 AC XY: 23948 AN XY: 74194

African (AFR) AF: 0.492 AC: 20411 AN: 41448

American (AMR) AF: 0.316 AC: 4816 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 920 AN: 3464

East Asian (EAS) AF: 0.536 AC: 2744 AN: 5124

South Asian (SAS) AF: 0.287 AC: 1363 AN: 4752

European-Finnish (FIN) AF: 0.196 AC: 2067 AN: 10550

Middle Eastern (MID) AF: 0.240 AC: 70 AN: 292

European-Non Finnish (NFE) AF: 0.238 AC: 16134 AN: 67912

Other (OTH) AF: 0.313 AC: 662 AN: 2112

Alfa AF: 0.294 Hom.: 887

Bravo AF: 0.343

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.1
DANN	Benign	0.49
PhyloP100		-3.7
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: rs4641527; hg19: chr12-72334683;