Variant 3-129976009-G-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 ENST00000302649.4(TRH):c.193G>C(p.Asp65His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

TRH
ENST00000302649.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.758

Variant links:

Genes affected

TRH (HGNC:12298): (thyrotropin releasing hormone) This gene encodes a member of the thyrotropin-releasing hormone family. Cleavage of the encoded proprotein releases mature thyrotropin-releasing hormone, which is a tripeptide hypothalamic regulatory hormone. The human proprotein contains six thyrotropin-releasing hormone tripeptides. Thyrotropin-releasing hormone is involved in the regulation and release of thyroid-stimulating hormone, as well as prolactin. Deficiency of this hormone has been associated with hypothalamic hypothyroidism. [provided by RefSeq, May 2013]

TRH links:

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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=0.1971815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRH	NM_007117.5 linkuse as main transcript	c.193G>C	p.Asp65His	missense_variant	2/3	ENST00000302649.4	NP_009048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRH	ENST00000302649.4 linkuse as main transcript	c.193G>C	p.Asp65His	missense_variant	2/3	1	NM_007117.5	ENSP00000303452	P2
TRH	ENST00000507066.1 linkuse as main transcript	c.193G>C	p.Asp65His	missense_variant	2/3	5		ENSP00000426522	A1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461714

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727148

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:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Apr 23, 2024

The c.193G>C (p.D65H) alteration is located in exon 2 (coding exon 1) of the TRH gene. This alteration results from a G to C substitution at nucleotide position 193, causing the aspartic acid (D) at amino acid position 65 to be replaced by a histidine (H). 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

0.14

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

T;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.53

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.3

M;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.9

D;N

REVEL

Benign

0.065

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.96

D;.

Vest4

0.24

MutPred

0.47

Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);

MVP

0.66

MPC

0.50

ClinPred

0.89

GERP RS

1.3

Varity_R

0.13

gMVP

0.10

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