rs144900788
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP3BP4_ModerateBS2_Supporting
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
Consequence
NM_000406.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000736 AC: 112AN: 152116Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00127 AC: 318AN: 250818Hom.: 1 AF XY: 0.00113 AC XY: 153AN XY: 135544
GnomAD4 exome AF: 0.00109 AC: 1600AN: 1461494Hom.: 3 Cov.: 31 AF XY: 0.00105 AC XY: 767AN XY: 727076
GnomAD4 genome AF: 0.000729 AC: 111AN: 152234Hom.: 1 Cov.: 32 AF XY: 0.000604 AC XY: 45AN XY: 74442
ClinVar
Submissions by phenotype
Hypogonadotropic hypogonadism 7 with or without anosmia Uncertain:3
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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. -
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not provided Uncertain:1Benign:1
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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) -
not specified Uncertain:1
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at