Genetic Variant TRHDE:p.Pro129Leu (chr12-72273029-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_013381.3(TRHDE):c.386C>T(p.Pro129Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000217 in 1,385,150 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: not found (cov: 32)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

TRHDE
NM_013381.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.88

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1869978).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013381.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRHDE	NM_013381.3	MANE Select	c.386C>T	p.Pro129Leu	missense	Exon 1 of 19	NP_037513.2	Q9UKU6
TRHDE-AS1	NR_026836.1		n.481G>A		non_coding_transcript_exon	Exon 1 of 3
TRHDE-AS1	NR_026837.1		n.481G>A		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRHDE	ENST00000261180.10	TSL:1 MANE Select	c.386C>T	p.Pro129Leu	missense	Exon 1 of 19	ENSP00000261180.5	Q9UKU6
TRHDE	ENST00000547300.2	TSL:3	c.386C>T	p.Pro129Leu	missense	Exon 1 of 5	ENSP00000447822.2	A0AA75K8V0
TRHDE-AS1	ENST00000426250.4	TSL:5	n.1005G>A		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000219

AC:

AN:

137246

AF XY:

0.0000133

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000274

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000217

AC:

AN:

1385150

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

683546

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31590

American (AMR)

AF:

0.00

AC:

AN:

36190

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25086

East Asian (EAS)

AF:

0.0000557

AC:

AN:

35938

South Asian (SAS)

AF:

0.00

AC:

AN:

79496

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34904

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5236

European-Non Finnish (NFE)

AF:

9.27e-7

AC:

AN:

1078914

Other (OTH)

AF:

0.00

AC:

AN:

57796

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.086

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.0070

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.75

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.66

MutationAssessor

Benign

0.81

PhyloP100

3.9

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.21

REVEL

Benign

0.078

Sift

Benign

0.070

Sift4G

Uncertain

0.021

Polyphen

0.31

Vest4

0.45

MutPred

0.27

Gain of catalytic residue at G79 (P = 0)

MVP

0.39

MPC

1.2

ClinPred

0.15

GERP RS

5.0

Varity_R

0.093

gMVP

0.61

Mutation Taster

=73/27

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over