Genetic Variant TRHDE:p.Ala65Val (chr12-72272837-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_013381.3(TRHDE):c.194C>T(p.Ala65Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A65S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TRHDE
NM_013381.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.57

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2799318).

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.194C>T	p.Ala65Val	missense	Exon 1 of 19	NP_037513.2	Q9UKU6
TRHDE-AS1	NR_026836.1		n.673G>A		non_coding_transcript_exon	Exon 1 of 3
TRHDE-AS1	NR_026837.1		n.673G>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.194C>T	p.Ala65Val	missense	Exon 1 of 19	ENSP00000261180.5	Q9UKU6
TRHDE	ENST00000547300.2	TSL:3	c.194C>T	p.Ala65Val	missense	Exon 1 of 5	ENSP00000447822.2	A0AA75K8V0
TRHDE-AS1	ENST00000426250.4	TSL:5	n.1197G>A		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1428872

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

708444

African (AFR)

AF:

0.00

AC:

AN:

33194

American (AMR)

AF:

0.00

AC:

AN:

43078

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25752

East Asian (EAS)

AF:

0.00

AC:

AN:

38986

South Asian (SAS)

AF:

0.00

AC:

AN:

83568

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5156

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102150

Other (OTH)

AF:

0.00

AC:

AN:

59408

GnomAD4 genome

Cov.:

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

0.15

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.87

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.67

MutationAssessor

Benign

0.90

PhyloP100

3.6

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.85

REVEL

Benign

0.12

Sift

Uncertain

0.012

Sift4G

Pathogenic

0.0

Polyphen

0.76

Vest4

0.24

MutPred

0.26

Gain of catalytic residue at W19 (P = 0.0055)

MVP

0.44

MPC

2.4

ClinPred

0.83

GERP RS

4.0

PromoterAI

-0.013

Neutral

(source)

Varity_R

0.36

gMVP

0.86

Mutation Taster

=72/28

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over