12-71994594-G-T

Position:

• chr12-71994594-G-T

Variant summary

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

The NM_173353.4(TPH2):​c.1068+29G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.854 in 1,612,220 control chromosomes in the GnomAD database, including 588,440 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 0.85 (54709 hom., cov: 32)
  • Exomes 𝑓: 0.85 (533731 hom.)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.145

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 = 0.936 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPH2	NM_173353.4	c.1068+29G>T		intron_variant		ENST00000333850.4	NP_775489.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPH2	ENST00000333850.4	c.1068+29G>T		intron_variant		1	NM_173353.4	ENSP00000329093	P1

Frequencies

GnomAD3 genomes AF: 0.847 AC: 128800 AN: 152046 Hom.: 54658 Cov.: 32

Gnomad AFR AF: 0.813

Gnomad AMI AF: 0.914

Gnomad AMR AF: 0.883

Gnomad ASJ AF: 0.870

Gnomad EAS AF: 0.959

Gnomad SAS AF: 0.913

Gnomad FIN AF: 0.825

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.848

Gnomad OTH AF: 0.855

GnomAD3 exomes AF: 0.873 AC: 219012 AN: 250926 Hom.: 95881 AF XY: 0.873 AC XY: 118380 AN XY: 135614

Gnomad AFR exome AF: 0.820

Gnomad AMR exome AF: 0.925

Gnomad ASJ exome AF: 0.883

Gnomad EAS exome AF: 0.955

Gnomad SAS exome AF: 0.911

Gnomad FIN exome AF: 0.836

Gnomad NFE exome AF: 0.847

Gnomad OTH exome AF: 0.863

GnomAD4 exome AF: 0.854 AC: 1247414 AN: 1460056 Hom.: 533731 Cov.: 36 AF XY: 0.855 AC XY: 621378 AN XY: 726374

Gnomad4 AFR exome AF: 0.817

Gnomad4 AMR exome AF: 0.918

Gnomad4 ASJ exome AF: 0.884

Gnomad4 EAS exome AF: 0.966

Gnomad4 SAS exome AF: 0.908

Gnomad4 FIN exome AF: 0.837

Gnomad4 NFE exome AF: 0.845

Gnomad4 OTH exome AF: 0.855

GnomAD4 genome AF: 0.847 AC: 128910 AN: 152164 Hom.: 54709 Cov.: 32 AF XY: 0.849 AC XY: 63181 AN XY: 74388

Gnomad4 AFR AF: 0.813

Gnomad4 AMR AF: 0.884

Gnomad4 ASJ AF: 0.870

Gnomad4 EAS AF: 0.958

Gnomad4 SAS AF: 0.914

Gnomad4 FIN AF: 0.825

Gnomad4 NFE AF: 0.848

Gnomad4 OTH AF: 0.856

Alfa AF: 0.852 Hom.: 17236

Bravo AF: 0.849

Asia WGS AF: 0.922 AC: 3205 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.5
DANN	Benign	0.42

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: rs1007023; hg19: chr12-72388374; COSMIC: COSV61594791;