Variant 12-72563025-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_013381.3(TRHDE):c.2027A>G(p.Lys676Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000254 in 1,595,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

TRHDE
NM_013381.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.426

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05873272).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRHDE	NM_013381.3 linkuse as main transcript	c.2027A>G	p.Lys676Arg	missense_variant	9/19	ENST00000261180.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
TRHDE	ENST00000261180.10 linkuse as main transcript	c.2027A>G	p.Lys676Arg	missense_variant	9/19	1	NM_013381.3	P1
TRHDE	ENST00000549138.5 linkuse as main transcript	n.456A>G		non_coding_transcript_exon_variant	3/7	5
TRHDE	ENST00000549401.5 linkuse as main transcript	n.174A>G		non_coding_transcript_exon_variant	1/5	3

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000427

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000172

AC:

AN:

238992

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

129428

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:

0.000352

Gnomad OTH exome

AF:

0.000344

GnomAD4 exome

AF:

0.000260

AC:

376

AN:

1443612

Hom.:

Cov.:

AF XY:

0.000264

AC XY:

190

AN XY:

718576

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000187

Gnomad4 NFE exome

AF:

0.000334

Gnomad4 OTH exome

AF:

0.000117

GnomAD4 genome

AF:

0.000191

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000427

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000244

Hom.:

Bravo

AF:

0.000128

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.000110

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 06, 2021

The c.1892A>G (p.K631R) alteration is located in exon 9 (coding exon 9) of the TRHDE gene. This alteration results from a A to G substitution at nucleotide position 1892, causing the lysine (K) at amino acid position 631 to be replaced by an arginine (R). 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

0.070

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.75

Cadd

Benign

9.3

Dann

Benign

0.15

DEOGEN2

Benign

0.11

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.50

M_CAP

Benign

0.0055

MetaRNN

Benign

0.059

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.94

MutationTaster

Benign

1.0

PrimateAI

Benign

0.25

PROVEAN

Benign

0.18

REVEL

Benign

0.045

Sift

Benign

0.47

Sift4G

Benign

0.34

Polyphen

0.0010

Vest4

0.097

MVP

0.11

MPC

0.31

ClinPred

0.020

GERP RS

2.3

Varity_R

0.052

gMVP

0.35

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over