12-71993562-C-T

Variant names:

• chr12-71993562-C-T
• rs4641528
• NM_173353.4:c.942-877C>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.942-877C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.511 in 151,944 control chromosomes in the GnomAD database, including 20,540 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 0.51 (20540 hom., cov: 32)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.191
• Publications: 6 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPH2	NM_173353.4	c.942-877C>T		intron_variant	Intron 7 of 10	ENST00000333850.4	NP_775489.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPH2	ENST00000333850.4	c.942-877C>T		intron_variant	Intron 7 of 10	1	NM_173353.4	ENSP00000329093.3

Frequencies

GnomAD3 genomes AF: 0.511 AC: 77572 AN: 151828 Hom.: 20528 Cov.: 32

Gnomad AFR AF: 0.369

Gnomad AMI AF: 0.629

Gnomad AMR AF: 0.528

Gnomad ASJ AF: 0.625

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.528

Gnomad FIN AF: 0.564

Gnomad MID AF: 0.583

Gnomad NFE AF: 0.578

Gnomad OTH AF: 0.544

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

GnomAD4 genome AF: 0.511 AC: 77608 AN: 151944 Hom.: 20540 Cov.: 32 AF XY: 0.511 AC XY: 37979 AN XY: 74254

African (AFR) AF: 0.368 AC: 15269 AN: 41436

American (AMR) AF: 0.528 AC: 8068 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.625 AC: 2169 AN: 3472

East Asian (EAS) AF: 0.473 AC: 2431 AN: 5140

South Asian (SAS) AF: 0.530 AC: 2552 AN: 4818

European-Finnish (FIN) AF: 0.564 AC: 5956 AN: 10552

Middle Eastern (MID) AF: 0.582 AC: 170 AN: 292

European-Non Finnish (NFE) AF: 0.578 AC: 39270 AN: 67940

Other (OTH) AF: 0.544 AC: 1149 AN: 2114

Alfa AF: 0.535 Hom.: 3867

Bravo AF: 0.502

Asia WGS AF: 0.489 AC: 1700 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.1
DANN	Benign	0.62
PhyloP100		0.19
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: rs4641528; hg19: chr12-72387342;