12-72112507-G-T

Position:

• chr12-72112507-G-T

Variant summary

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

The XM_017019244.2(TRHDE):​c.-131+6755G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.755 in 152,120 control chromosomes in the GnomAD database, including 44,013 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 0.76 (44013 hom., cov: 33)
• Consequence: TRHDE XM_017019244.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.211

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.814 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRHDE	XM_017019244.2	c.-131+6755G>T		intron_variant			XP_016874733.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPH2	ENST00000547278.1	n.596+36799G>T		intron_variant, non_coding_transcript_variant		3
TPH2	ENST00000547348.5	n.203-55031G>T		intron_variant, non_coding_transcript_variant		3
TRHDE	ENST00000548156.1	n.279+6755G>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.755 AC: 114798 AN: 152000 Hom.: 43980 Cov.: 33

Gnomad AFR AF: 0.647

Gnomad AMI AF: 0.687

Gnomad AMR AF: 0.739

Gnomad ASJ AF: 0.775

Gnomad EAS AF: 0.643

Gnomad SAS AF: 0.704

Gnomad FIN AF: 0.864

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.820

Gnomad OTH AF: 0.759

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

GnomAD4 genome AF: 0.755 AC: 114893 AN: 152120 Hom.: 44013 Cov.: 33 AF XY: 0.758 AC XY: 56361 AN XY: 74358

Gnomad4 AFR AF: 0.647

Gnomad4 AMR AF: 0.740

Gnomad4 ASJ AF: 0.775

Gnomad4 EAS AF: 0.643

Gnomad4 SAS AF: 0.706

Gnomad4 FIN AF: 0.864

Gnomad4 NFE AF: 0.819

Gnomad4 OTH AF: 0.753

Alfa AF: 0.787 Hom.: 5881

Bravo AF: 0.739

Asia WGS AF: 0.643 AC: 2238 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.71
DANN	Benign	0.21

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2220159; hg19: chr12-72506287;