chr1-65570525-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_002303.6(LEPR):c.93G>A(p.Trp31Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,718 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 (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
LEPR
NM_002303.6 stop_gained
NM_002303.6 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 3.51
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 Pathogenic. Variant got 14 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 18 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-65570525-G-A is Pathogenic according to our data. Variant chr1-65570525-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 421140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LEPR | NM_002303.6 | c.93G>A | p.Trp31Ter | stop_gained | 4/20 | ENST00000349533.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LEPR | ENST00000349533.11 | c.93G>A | p.Trp31Ter | stop_gained | 4/20 | 1 | NM_002303.6 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152136Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461582Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727088
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152136Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74312
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 18, 2024 | 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 28432296, 27397505, 30560226, 17229951) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 20, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 22, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 421140). This premature translational stop signal has been observed in individual(s) with severe early-onset obesity (PMID: 17229951). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp31*) in the LEPR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LEPR are known to be pathogenic (PMID: 23616257, 24319006, 25751111). - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A;A;D
Vest4
GERP RS
Splicing
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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