12-72104411-A-G

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The XM_017019244.2(TRHDE):​c.-235-1237A>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: TRHDE XM_017019244.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.73

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRHDE	XM_017019244.2	c.-235-1237A>G		intron_variant	Intron 1 of 19		XP_016874733.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPH2	ENST00000547278.1	n.596+28703A>G		intron_variant	Intron 5 of 5	3
TPH2	ENST00000547348.5	n.202+56754A>G		intron_variant	Intron 2 of 3	3
TRHDE	ENST00000548156.1	n.175-1237A>G		intron_variant	Intron 1 of 4	4

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

Gnomad4 AFR AF: 0.528

Gnomad4 AMR AF: 0.720

Gnomad4 ASJ AF: 0.774

Gnomad4 EAS AF: 0.642

Gnomad4 SAS AF: 0.692

Gnomad4 FIN AF: 0.858

Gnomad4 NFE AF: 0.808

Gnomad4 OTH AF: 0.712

Alfa AF: 0.748 Hom.: 6337

Bravo AF: 0.694

Asia WGS AF: 0.631 AC: 2196 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs6582086; hg19: chr12-72498191;