rs144900788

chr4-67753900-G-Achr4-67753900-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM1 PP3 BP4_Moderate

The NM_000406.3(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 NM_000406.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 9.91

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 Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a disulfide_bond (size 82) in uniprot entity GNRHR_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_000406.3
• 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).

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152116 Hom.: 1 Cov.: 32

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.: 1 AF XY: 0.00113 AC XY: 153 AN XY: 135544

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.: 3 Cov.: 31 AF XY: 0.00105 AC XY: 767 AN XY: 727076

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.: 1 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74442

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.: 1

Bravo AF: 0.000854

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00131 AC: 159

EpiCase AF: 0.00153

EpiControl AF: 0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

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	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2017	The P146S variant has been published previously in patients with IHH, but only in the heterozygous state to our knowledge (Vagenakis et al., 2005; Sykiotis et al., 2010; Gianetti et al., 2012). The variant is observed in 69/11350 (0.61%) alleles from individuals of Latino background in the ExAC dataset (Lek et al., 2016). P146S is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	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, criteria provided, single submitter

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	T
BayesDel_noAF	Pathogenic	0.27
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
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	T
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

Other links and lift over

dbSNP: rs144900788; hg19: chr4-68619618;