Variant 12-72273506-A-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_013381.3(TRHDE):c.863A>C(p.Asn288Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000361 in 1,610,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

TRHDE
NM_013381.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.61

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:

TRHDE-AS1 (HGNC:27471): (TRHDE antisense RNA 1)

TRHDE-AS1 links:

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=0.16251421).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRHDE	NM_013381.3 linkuse as main transcript	c.863A>C	p.Asn288Thr	missense_variant	1/19	ENST00000261180.10
TRHDE-AS1	NR_026837.1 linkuse as main transcript	n.4T>G		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRHDE	ENST00000261180.10 linkuse as main transcript	c.863A>C	p.Asn288Thr	missense_variant	1/19	1	NM_013381.3	P1
TRHDE-AS1	ENST00000663912.1 linkuse as main transcript	n.134+3315T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000158

AC:

AN:

246396

Hom.:

AF XY:

0.000149

AC XY:

AN XY:

133882

show subpopulations

Gnomad AFR exome

AF:

0.000320

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:

0.0000525

Gnomad NFE exome

AF:

0.000276

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.000386

AC:

563

AN:

1457912

Hom.:

Cov.:

AF XY:

0.000368

AC XY:

267

AN XY:

725388

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.000121

Gnomad4 NFE exome

AF:

0.000491

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000118

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000293

Hom.:

Bravo

AF:

0.000178

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000356

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 12, 2021

The c.728A>C (p.N243T) alteration is located in exon 1 (coding exon 1) of the TRHDE gene. This alteration results from a A to C substitution at nucleotide position 728, causing the asparagine (N) at amino acid position 243 to be replaced by a threonine (T). 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

0.28

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.51

Cadd

Uncertain

Dann

Uncertain

0.98

DEOGEN2

Benign

0.12

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.069

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.024

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.30

MutationTaster

Benign

0.87

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-2.0

REVEL

Benign

0.18

Sift

Uncertain

0.0070

Sift4G

Benign

0.069

Polyphen

0.68

Vest4

0.48

MVP

0.37

MPC

0.86

ClinPred

0.10

GERP RS

4.1

Varity_R

0.19

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.

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