rs144292455
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001059.3(TACR3):c.824G>A(p.Trp275*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000463 in 1,612,902 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001059.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000375 AC: 57AN: 151984Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000307 AC: 77AN: 250942Hom.: 0 AF XY: 0.000295 AC XY: 40AN XY: 135610
GnomAD4 exome AF: 0.000472 AC: 690AN: 1460918Hom.: 0 Cov.: 31 AF XY: 0.000466 AC XY: 339AN XY: 726780
GnomAD4 genome AF: 0.000375 AC: 57AN: 151984Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21AN XY: 74214
ClinVar
Submissions by phenotype
not provided Pathogenic:4
This sequence change creates a premature translational stop signal (p.Trp275*) in the TACR3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TACR3 are known to be pathogenic (PMID: 20194706, 20332248, 22031817). This variant is present in population databases (rs144292455, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with idiopathic hypogonadotropic hypogonadism (PMID: 33363893). ClinVar contains an entry for this variant (Variation ID: 66084). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
DNA sequence analysis of the TACR3 gene demonstrated an apparently homozygous sequence change, c.824G>A, which results in the creation of a premature stop codon at amino acid position 275, p.Trp275*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated TACR3 protein with potentially abnormal function. This sequence change has been previously described in male patients with normosmic idiopathic hypogonadotropic hypogonadism in both homozygous and compound heterozygous state (Francou et al., 2011 and Gianetti et al., 2010). This sequence change has been described in the gnomAD database with a population frequency of 0.032% (rs144292455). -
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Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29419413, 29886503, 31200363, 23643382, 21300340, 25525159, 26207952, 28436984, 30665703, 23329188, 30450471, 20332248, 26792935, 26239645, 22035731, 31980526, 34426522, 33363893, 31589614, 34055685, 22031817) -
Hypogonadotropic hypogonadism 11 with or without anosmia Pathogenic:3
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The TACR3 c.824G>A (p.Trp275Ter) variant is a stop-gained variant reported in four studies in which it is found in a total of 13 individuals with isolated gonadotropin-releasing hormone (GnRH) deficiency, including in three homozygotes, in three compound heterozygotes, in five heterozygotes, and in two individuals showing digenic inheritance (Gianetti et al. 2010; Quaynor et al. 2011; Xu et al. 2011; Francou et al. 2011). The variant was absent from over 800 controls, but is reported at a frequency of 0.00093 in the European American population of the Exome Sequencing Project. Based on the potential impact of stop-gained variants and the evidence from the literature, the p.Trp275Ter 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. -
TACR3-related disorder Pathogenic:1
The TACR3 c.824G>A variant is predicted to result in premature protein termination (p.Trp275*). This variant has been reported in the compound heterozygous and homozygous states, as well as in combination with variants in other genes, to be causative for hypogonadotropic hypogonadism (see for example - Gianetti et al. 2010. PubMed ID: 20332248; Xu et al. 2011. PubMed ID: 21300340). This variant is reported in 0.065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in TACR3 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at