rs1805096
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_002303.6(LEPR):c.3057G>A(p.Pro1019=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 1,613,714 control chromosomes in the GnomAD database, including 139,816 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.44 ( 15242 hom., cov: 32)
Exomes 𝑓: 0.40 ( 124574 hom. )
Consequence
LEPR
NM_002303.6 synonymous
NM_002303.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.823
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 Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.95).
BP6
?
Variant 1-65636574-G-A is Benign according to our data. Variant chr1-65636574-G-A is described in ClinVar as [Benign]. Clinvar id is 298000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-65636574-G-A is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-0.823 with no splicing effect.
BA1
?
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.849 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LEPR | NM_002303.6 | c.3057G>A | p.Pro1019= | synonymous_variant | 20/20 | ENST00000349533.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LEPR | ENST00000349533.11 | c.3057G>A | p.Pro1019= | synonymous_variant | 20/20 | 1 | NM_002303.6 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.437 AC: 66340AN: 151842Hom.: 15210 Cov.: 32
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GnomAD3 exomes AF: 0.457 AC: 114099AN: 249416Hom.: 28262 AF XY: 0.452 AC XY: 61090AN XY: 135292
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GnomAD4 exome AF: 0.403 AC: 589205AN: 1461754Hom.: 124574 Cov.: 69 AF XY: 0.404 AC XY: 293419AN XY: 727172
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GnomAD4 genome ? AF: 0.437 AC: 66434AN: 151960Hom.: 15242 Cov.: 32 AF XY: 0.446 AC XY: 33101AN XY: 74280
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ClinVar
Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Obesity due to leptin receptor gene deficiency Benign:3
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 10, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
not specified Benign:2
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 26, 2017 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 05, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Monogenic Non-Syndromic Obesity Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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