12-72104411-A-G

Variant names:

• chr12-72104411-A-G
• rs6582086
• XM_017019244.2:c.-235-1237A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The ENST00000547278.1(TPH2):​n.596+28703A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.714 in 152,064 control chromosomes in the GnomAD database, including 40,072 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 0.71 (40072 hom., cov: 31)
• Consequence: TPH2 ENST00000547278.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.73
• Publications: 6 publications found

Genes affected

TRHDE (HGNC:30748): (thyrotropin releasing hormone degrading enzyme) This gene encodes a member of the peptidase M1 family. The encoded protein is an extracellular peptidase that specifically cleaves and inactivates the neuropeptide thyrotropin-releasing hormone.[provided by RefSeq, Dec 2008]

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]

TPH2 Gene-Disease associations (from GenCC):

• attention deficit-hyperactivity disorder, susceptibility to, 7

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.803 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000547278.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPH2	ENST00000547278.1	TSL:3	n.596+28703A>G		intron	N/A
	TPH2	ENST00000547348.5	TSL:3	n.202+56754A>G		intron	N/A
	TRHDE	ENST00000548156.1	TSL:4	n.175-1237A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.714 AC: 108517 AN: 151946 Hom.: 40055 Cov.: 31

Gnomad AFR AF: 0.528

Gnomad AMI AF: 0.637

Gnomad AMR AF: 0.719

Gnomad ASJ AF: 0.774

Gnomad EAS AF: 0.642

Gnomad SAS AF: 0.690

Gnomad FIN AF: 0.858

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.809

Gnomad OTH AF: 0.718

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

GnomAD4 genome AF: 0.714 AC: 108584 AN: 152064 Hom.: 40072 Cov.: 31 AF XY: 0.718 AC XY: 53356 AN XY: 74356

African (AFR) AF: 0.528 AC: 21885 AN: 41426

American (AMR) AF: 0.720 AC: 11007 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.774 AC: 2686 AN: 3472

East Asian (EAS) AF: 0.642 AC: 3313 AN: 5160

South Asian (SAS) AF: 0.692 AC: 3336 AN: 4818

European-Finnish (FIN) AF: 0.858 AC: 9089 AN: 10596

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.808 AC: 54966 AN: 67986

Other (OTH) AF: 0.712 AC: 1505 AN: 2114

Alfa AF: 0.741 Hom.: 6460

Bravo AF: 0.694

Asia WGS AF: 0.631 AC: 2196 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Benign	0.78
PhyloP100		2.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6582086; hg19: chr12-72498191;