rs756571131
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4
The NM_002303.6(LEPR):c.3495_3496delGT(p.Ter1166fs) variant causes a frameshift, stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,154 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
LEPR
NM_002303.6 frameshift, stop_lost
NM_002303.6 frameshift, stop_lost
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.77
Genes affected
LEPR (HGNC:6554): (leptin receptor) The protein encoded by this gene belongs to the gp130 family of cytokine receptors that are known to stimulate gene transcription via activation of cytosolic STAT proteins. This protein is a receptor for leptin (an adipocyte-specific hormone that regulates body weight), and is involved in the regulation of fat metabolism, as well as in a novel hematopoietic pathway that is required for normal lymphopoiesis. Mutations in this gene have been associated with obesity and pituitary dysfunction. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. It is noteworthy that this gene and LEPROT gene (GeneID:54741) share the same promoter and the first 2 exons, however, encode distinct proteins (PMID:9207021).[provided by RefSeq, Nov 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Stoplost variant in NM_002303.6 Downstream stopcodon found after 56 codons.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LEPR | NM_002303.6 | c.3495_3496delGT | p.Ter1166fs | frameshift_variant, stop_lost | 20/20 | ENST00000349533.11 | NP_002294.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LEPR | ENST00000349533.11 | c.3495_3496delGT | p.Ter1166fs | frameshift_variant, stop_lost | 20/20 | 1 | NM_002303.6 | ENSP00000330393.7 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152146Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000362 AC: 9AN: 248412Hom.: 0 AF XY: 0.0000446 AC XY: 6AN XY: 134668
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GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461008Hom.: 0 AF XY: 0.00000825 AC XY: 6AN XY: 726834
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74330
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 21, 2017 | - - |
LEPR-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 23, 2024 | The LEPR c.3495_3496delGT variant is predicted to result in extension of the open reading frame (p.*1166Ileext*13). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 07, 2022 | This variant has not been reported in the literature in individuals affected with LEPR-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 435748). This variant is present in population databases (rs756571131, gnomAD 0.01%). This sequence change disrupts the translational stop signal of the LEPR mRNA. It is expected to extend the length of the LEPR protein by 13 additional amino acid residues. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at