12-72273151-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_013381.3(TRHDE):​c.508C>T​(p.Pro170Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000381 in 1,573,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

TRHDE
NM_013381.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.20
Variant links:
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]
TRHDE-AS1 (HGNC:27471): (TRHDE antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.1121127).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TRHDENM_013381.3 linkc.508C>T p.Pro170Ser missense_variant Exon 1 of 19 ENST00000261180.10 NP_037513.2 Q9UKU6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TRHDEENST00000261180.10 linkc.508C>T p.Pro170Ser missense_variant Exon 1 of 19 1 NM_013381.3 ENSP00000261180.5 Q9UKU6

Frequencies

GnomAD3 genomes
AF:
0.0000264
AC:
4
AN:
151626
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000442
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000467
AC:
1
AN:
214034
Hom.:
0
AF XY:
0.00000853
AC XY:
1
AN XY:
117240
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000105
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000394
AC:
56
AN:
1421504
Hom.:
0
Cov.:
33
AF XY:
0.0000342
AC XY:
24
AN XY:
701980
show subpopulations
Gnomad4 AFR exome
AF:
0.0000305
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000468
Gnomad4 OTH exome
AF:
0.0000681
GnomAD4 genome
AF:
0.0000264
AC:
4
AN:
151626
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74040
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000442
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189
ExAC
AF:
0.00000830
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 19, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.373C>T (p.P125S) alteration is located in exon 1 (coding exon 1) of the TRHDE gene. This alteration results from a C to T substitution at nucleotide position 373, causing the proline (P) at amino acid position 125 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.064
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
22
DANN
Benign
0.97
DEOGEN2
Benign
0.076
T
Eigen
Benign
-0.43
Eigen_PC
Benign
-0.24
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.72
T
M_CAP
Benign
0.034
D
MetaRNN
Benign
0.11
T
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
0.90
L
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-0.19
N
REVEL
Benign
0.066
Sift
Benign
0.070
T
Sift4G
Benign
0.15
T
Polyphen
0.0080
B
Vest4
0.21
MutPred
0.32
Gain of phosphorylation at P125 (P = 0.0083);
MVP
0.30
MPC
1.2
ClinPred
0.14
T
GERP RS
2.9
Varity_R
0.068
gMVP
0.58

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs767570436; hg19: chr12-72666931; API