12-72004363-A-G

Variant names:

• chr12-72004363-A-G
• rs1386498
• NM_173353.4:c.1068+9798A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173353.4(TPH2):​c.1068+9798A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.531 in 149,950 control chromosomes in the GnomAD database, including 22,955 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 0.53 (22955 hom., cov: 32)
• Consequence: TPH2 NM_173353.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.37
• Publications: 3 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 (SAS) allele frequency at 95% confidence interval = 0.595 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPH2	NM_173353.4	c.1068+9798A>G		intron_variant	Intron 8 of 10	ENST00000333850.4	NP_775489.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPH2	ENST00000333850.4	c.1068+9798A>G		intron_variant	Intron 8 of 10	1	NM_173353.4	ENSP00000329093.3

Frequencies

GnomAD3 genomes AF: 0.532 AC: 79648 AN: 149838 Hom.: 22940 Cov.: 32

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.680

Gnomad AMR AF: 0.587

Gnomad ASJ AF: 0.632

Gnomad EAS AF: 0.548

Gnomad SAS AF: 0.614

Gnomad FIN AF: 0.498

Gnomad MID AF: 0.616

Gnomad NFE AF: 0.578

Gnomad OTH AF: 0.562

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

GnomAD4 genome AF: 0.531 AC: 79692 AN: 149950 Hom.: 22955 Cov.: 32 AF XY: 0.531 AC XY: 38791 AN XY: 73004

African (AFR) AF: 0.419 AC: 17225 AN: 41124

American (AMR) AF: 0.588 AC: 8655 AN: 14728

Ashkenazi Jewish (ASJ) AF: 0.632 AC: 2185 AN: 3460

East Asian (EAS) AF: 0.549 AC: 2679 AN: 4882

South Asian (SAS) AF: 0.614 AC: 2719 AN: 4426

European-Finnish (FIN) AF: 0.498 AC: 5164 AN: 10378

Middle Eastern (MID) AF: 0.622 AC: 179 AN: 288

European-Non Finnish (NFE) AF: 0.578 AC: 39098 AN: 67682

Other (OTH) AF: 0.565 AC: 1171 AN: 2074

Alfa AF: 0.561 Hom.: 8119

Asia WGS AF: 0.584 AC: 1945 AN: 3326

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.065
DANN	Benign	0.42
PhyloP100		-2.4
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: rs1386498; hg19: chr12-72398143;