Variant 4-67753825-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate

The NM_000406.3(GNRHR):c.511G>A(p.Ala171Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

GNRHR
NM_000406.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 3.71

Variant links:

Genes affected

GNRHR (HGNC:4421): (gonadotropin releasing hormone receptor) This gene encodes the receptor for type 1 gonadotropin-releasing hormone. This receptor is a member of the seven-transmembrane, G-protein coupled receptor (GPCR) family. It is expressed on the surface of pituitary gonadotrope cells as well as lymphocytes, breast, ovary, and prostate. Following binding of gonadotropin-releasing hormone, the receptor associates with G-proteins that activate a phosphatidylinositol-calcium second messenger system. Activation of the receptor ultimately causes the release of gonadotropic luteinizing hormone (LH) and follicle stimulating hormone (FSH). Defects in this gene are a cause of hypogonadotropic hypogonadism (HH). Alternative splicing results in multiple transcript variants encoding different isoforms. More than 18 transcription initiation sites in the 5' region and multiple polyA signals in the 3' region have been identified for this gene. [provided by RefSeq, Jul 2008]

GNRHR links:

UBA6-DT (HGNC:):

UBA6-DT links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.78

PP5

Variant 4-67753825-C-T is Pathogenic according to our data. Variant chr4-67753825-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16034.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNRHR	NM_000406.3 linkuse as main transcript	c.511G>A	p.Ala171Thr	missense_variant	1/3	ENST00000226413.5	NP_000397.1	P30968-1
GNRHR	NM_001012763.2 linkuse as main transcript	c.511G>A	p.Ala171Thr	missense_variant	1/3		NP_001012781.1	P30968-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNRHR	ENST00000226413.5 linkuse as main transcript	c.511G>A	p.Ala171Thr	missense_variant	1/3	1	NM_000406.3	ENSP00000226413.5		P30968-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249714

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460932

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726718

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000333

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 7 with or without anosmia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 23, 2020	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4_MOD,PM2,PM3,PP2,PP3,PP4. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2003	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

D;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.057

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.7

M;M

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.7

D;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.95

P;D

Vest4

0.85

MVP

0.71

MPC

0.32

ClinPred

0.92

GERP RS

5.9

Varity_R

0.37

gMVP

0.76

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