rs144900788

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM1PP3BP4_ModerateBS2_Supporting

The ENST00000226413.5(GNRHR):c.436C>T(p.Pro146Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,613,728 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00073 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 3 hom. )

Consequence

GNRHR
ENST00000226413.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 9.91

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:49083): (UBA6 divergent transcript)

UBA6-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 26) in uniprot entity GNRHR_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in ENST00000226413.5

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, M_CAP, MetaRNN, MutationTaster, PrimateAI was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.10779202).

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR,Digenic geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNRHR	NM_000406.3 linkuse as main transcript	c.436C>T	p.Pro146Ser	missense_variant	1/3	ENST00000226413.5	NP_000397.1
GNRHR	NM_001012763.2 linkuse as main transcript	c.436C>T	p.Pro146Ser	missense_variant	1/3		NP_001012781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNRHR	ENST00000226413.5 linkuse as main transcript	c.436C>T	p.Pro146Ser	missense_variant	1/3	1	NM_000406.3	ENSP00000226413	P1	P30968-1
UBA6-DT	ENST00000500538.7 linkuse as main transcript	n.1921-1289G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.000736

AC:

112

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00125

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00115

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.00127

AC:

318

AN:

250818

Hom.:

AF XY:

0.00113

AC XY:

153

AN XY:

135544

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00386

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000694

Gnomad NFE exome

AF:

0.00119

Gnomad OTH exome

AF:

0.00524

GnomAD4 exome

AF:

0.00109

AC:

1600

AN:

1461494

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

767

AN XY:

727076

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00378

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000805

Gnomad4 NFE exome

AF:

0.00119

Gnomad4 OTH exome

AF:

0.000894

GnomAD4 genome

AF:

0.000729

AC:

111

AN:

152234

Hom.:

Cov.:

AF XY:

0.000604

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00113

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00105

Hom.:

Bravo

AF:

0.000854

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00131

AC:

159

EpiCase

AF:

0.00153

EpiControl

AF:

0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 7 with or without anosmia

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 15, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2024	Reported in the published literature in association with hypogonadotropic hypogonadism (PMID: 16359986, 22745237, 20696889, 34198905); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9425890, 16359986, 23643382, 22745237, 20389088, 20696889, 34426522, 22679506, 37958948, 21645587, 30575316, 27884859, 34198905, 34403359, 30921766, 36110220, 21736917) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 07, 2020

DNA sequence analysis of the GNRHR gene demonstrated a sequence change, c.436C>T, in exon 1 that results in an amino acid change, p.Pro146Ser. This sequence change has been described in the gnomAD database with a population frequency of 0.38% in Latino subpopulations and it has been observed in one individual in the homozygous state (dbSNP rs144900788). This sequence change was identified in the heterozygous state in individuals with normosmic idiopathic hypogonadotropic hypogonadism and Kallmann syndrome but a second pathogenic change in this gene was not identified (PMID: 22745237 and PMID: 16359986). The p.Pro146Ser change affects a highly conserved amino acid residue located in a domain of the GNRHR protein that is known to be functional. The p.Pro146Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro146Ser change remains unknown at this time. -

GNRHR-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 27, 2024

The GNRHR c.436C>T variant is predicted to result in the amino acid substitution p.Pro146Ser. This variant has been reported in the heterozygous state in several patients with hypogonadotropic hypogonadism/Kallmann syndrome (see, for example, Vagenakis et al. 2005. PubMed ID: 16359986; Gianetti et al. 2012. PubMed ID: 22745237; Miraoui et al. 2013. PubMed ID: 23643382, Table S3; Stamou et al. 2019. PubMed ID: 30921766), delayed puberty (Saengkaew et al. 2021. PubMed ID: 34403359), or a suspected disorder of sex development (Zidoune et al. 2022. PubMed ID: 36110220, supplementary data). However, a second pathogenic variant was not identified in these patients. In addition, no genetic or functional study has been performed to assess the pathogenicity of this variant. This variant has been observed with an allele frequency of up to ~0.38% in Latino individuals from a large population database, including 1 homozygote. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Uncertain

0.030

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.81

D;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.059

MetaRNN

Benign

0.11

T;T

MetaSVM

Uncertain

0.12

MutationAssessor

Pathogenic

3.1

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-7.8

D;D

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.97

MVP

0.90

MPC

0.35

ClinPred

0.15

GERP RS

6.2

Varity_R

0.91

gMVP

0.88

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