12-71968598-G-C

Position:

• chr12-71968598-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173353.4(TPH2):​c.609-3921G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 152,188 control chromosomes in the GnomAD database, including 3,209 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 0.19 (3209 hom., cov: 33)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0770

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPH2	NM_173353.4	c.609-3921G>C		intron_variant		ENST00000333850.4	NP_775489.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPH2	ENST00000333850.4	c.609-3921G>C		intron_variant		1	NM_173353.4	ENSP00000329093	P1

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28373 AN: 152070 Hom.: 3213 Cov.: 33

Gnomad AFR AF: 0.0541

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.343

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.194

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

GnomAD4 genome AF: 0.186 AC: 28361 AN: 152188 Hom.: 3209 Cov.: 33 AF XY: 0.187 AC XY: 13895 AN XY: 74430

Gnomad4 AFR AF: 0.0540

Gnomad4 AMR AF: 0.219

Gnomad4 ASJ AF: 0.219

Gnomad4 EAS AF: 0.343

Gnomad4 SAS AF: 0.204

Gnomad4 FIN AF: 0.215

Gnomad4 NFE AF: 0.240

Gnomad4 OTH AF: 0.192

Alfa AF: 0.107 Hom.: 177

Bravo AF: 0.183

Asia WGS AF: 0.215 AC: 746 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.72
DANN	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1386491; hg19: chr12-72362378; COSMIC: COSV61594342; COSMIC: COSV61594342;