rs104893842

chr4-67753920-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000406.3(GNRHR):c.416G>A(p.Arg139His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,613,080 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R139C) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: GNRHR NM_000406.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.83

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]

UBA6-DT (HGNC:49083): (UBA6 divergent transcript)

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000406.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-67753921-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1675193.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 4-67753920-C-T is Pathogenic according to our data. Variant chr4-67753920-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-67753920-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNRHR	NM_000406.3	c.416G>A	p.Arg139His	missense_variant	1/3	ENST00000226413.5
GNRHR	NM_001012763.2	c.416G>A	p.Arg139His	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNRHR	ENST00000226413.5	c.416G>A	p.Arg139His	missense_variant	1/3	1	NM_000406.3	P1
UBA6-DT	ENST00000500538.7	n.1921-1269C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000144 AC: 36 AN: 250806 Hom.: 0 AF XY: 0.0000959 AC XY: 13 AN XY: 135508

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000555

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000142 AC: 208 AN: 1460866 Hom.: 0 Cov.: 31 AF XY: 0.000144 AC XY: 105 AN XY: 726780

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000524

Gnomad4 NFE exome AF: 0.000152

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74404

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.000136

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypogonadotropic hypogonadism 7 with or without anosmia Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 14, 2016	The GNRHR c.416G>A (p.Arg139His) missense variant has been identified in a homozygous state in ten individuals and in a compound heterozygous state in at least 11 individuals with isolated gonadotropin-releasing hormone (GnRH) deficiency, and in a heterozygous state in five unaffected family members (Costa et al. 2001; Wolczynski et al. 2003; Laitinen et al. 2012; Gianetti et al. 2012; Hero et al. 2012; Gurbuz et al. 2012; Choi et al. 2015). The p.Arg139His variant was absent from 422 controls and is reported at a frequency of 0.00076 in the European (Finnish) population of the Exome Aggregation Consortium. Functional studies in COS-7 cells demonstrated normal localization of the mutant protein at the cell surface but complete elimination of GnRH-binding activity and activation of intracellular transduction pathways (Costa et al. 2001; Leanos-Miranda et al. 2002). Based on the evidence, the p.Arg139His variant is classified as pathogenic for isolated GnRH deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2001	- -
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, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 16, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Mar 01, 2023	- -

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 19, 2022	DNA sequence analysis of the GNRHR gene demonstrated a sequence change, c.416G>A , in exon 1 that results in an amino acid change, p.Arg139His. The p.Arg139His change affects a highly conserved amino acid residue located in a domain of the GNRHR protein that is known to be functional. The p.Arg139His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This pathogenic sequence change has previously been described in individuals with hypogonadotropic hypogonadism and is commonly reported in individuals of Brazilian ancestry (PMID: 11397871, 22724017, 25016926, 26207952, 27544332). This sequence change has been described in the gnomAD database with a frequency of 0.055% in the European subpopulation (dbSNP rs104893842). These collective evidences indicate that this sequence change is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 18, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 139 of the GNRHR protein (p.Arg139His). This variant is present in population databases (rs104893842, gnomAD 0.05%). This missense change has been observed in individuals with hypogonadotropic hypogonadism (PMID: 11397871, 22724017, 25016926, 26207952, 27544332). It is commonly reported in individuals of Brazilian ancestry (PMID: 11397871, 22724017, 25016926, 26207952, 27544332). ClinVar contains an entry for this variant (Variation ID: 16030). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GNRHR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GNRHR function (PMID: 11397871, 12364481). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 11, 2022	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: 12364481, 11397871, 26207952, 22745237, 32763379, 31589614, 26044071, 12667096, 23155690, 21645587, 34426522, 20207726, 16213849, 24117998, 21736917, 22766261, 25016926, 20389088, 14689055, 22405597, 21717411, 31200363, 30476149, 32222824, 27544332, 34198905) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		1.0
MVP		0.99
MPC		0.38
ClinPred		0.68	D
GERP RS		6.2
Varity_R		0.79
gMVP		0.95

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

Other links and lift over

dbSNP: rs104893842; hg19: chr4-68619638; COSMIC: COSV56934594;