Variant chr12-72286880-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The ENST00000261180.10(TRHDE):c.1114A>C(p.Met372Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TRHDE
ENST00000261180.10 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.75

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TRHDE	NM_013381.3 linkuse as main transcript	c.1114A>C	p.Met372Leu	missense_variant	2/19	ENST00000261180.10	NP_037513.2
TRHDE	XM_017019243.3 linkuse as main transcript	c.1114A>C	p.Met372Leu	missense_variant	2/18		XP_016874732.3
TRHDE	XM_005268819.6 linkuse as main transcript	c.1114A>C	p.Met372Leu	missense_variant	2/13		XP_005268876.3
TRHDE	XM_017019244.2 linkuse as main transcript	c.70A>C	p.Met24Leu	missense_variant	3/20		XP_016874733.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
TRHDE	ENST00000261180.10 linkuse as main transcript	c.1114A>C	p.Met372Leu	missense_variant	2/19	1	NM_013381.3	ENSP00000261180	P1
TRHDE	ENST00000547300.2 linkuse as main transcript	c.1114A>C	p.Met372Leu	missense_variant	2/5	3		ENSP00000447822
TRHDE	ENST00000552503.1 linkuse as main transcript	n.278A>C		non_coding_transcript_exon_variant	2/5	4
TRHDE	ENST00000548156.1 linkuse as main transcript	n.280-91115A>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.84e-7

AC:

AN:

1461632

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727118

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:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Oct 27, 2022

The c.979A>C (p.M327L) alteration is located in exon 2 (coding exon 2) of the TRHDE gene. This alteration results from a A to C substitution at nucleotide position 979, causing the methionine (M) at amino acid position 327 to be replaced by a leucine (L). 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

Pathogenic

0.73

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.029

MetaRNN

Pathogenic

0.75

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.48

Sift

Pathogenic

0.0

Sift4G

Benign

0.086

Polyphen

1.0

Vest4

0.74

MutPred

0.67

Gain of catalytic residue at L332 (P = 0);

MVP

0.63

MPC

1.1

ClinPred

0.99

GERP RS

6.2

Varity_R

0.79

gMVP

0.90

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over