chr7-128254434-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate
The NM_000230.3(LEP):c.175G>A(p.Gly59Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,670 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 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
LEP
NM_000230.3 missense
NM_000230.3 missense
Scores
4
13
2
Clinical Significance
Conservation
PhyloP100: 3.79
Genes affected
LEP (HGNC:6553): (leptin) This gene encodes a protein that is secreted by white adipocytes into the circulation and plays a major role in the regulation of energy homeostasis. Circulating leptin binds to the leptin receptor in the brain, which activates downstream signaling pathways that inhibit feeding and promote energy expenditure. This protein also has several endocrine functions, and is involved in the regulation of immune and inflammatory responses, hematopoiesis, angiogenesis, reproduction, bone formation and wound healing. Mutations in this gene and its regulatory regions cause severe obesity and morbid obesity with hypogonadism in human patients. A mutation in this gene has also been linked to type 2 diabetes mellitus development. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
In a chain Leptin (size 145) in uniprot entity LEP_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_000230.3
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.923
PP5
?
Variant 7-128254434-G-A is Pathogenic according to our data. Variant chr7-128254434-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2428497.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LEP | NM_000230.3 | c.175G>A | p.Gly59Ser | missense_variant | 3/3 | ENST00000308868.5 | |
LEP | XM_005250340.6 | c.172G>A | p.Gly58Ser | missense_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LEP | ENST00000308868.5 | c.175G>A | p.Gly59Ser | missense_variant | 3/3 | 1 | NM_000230.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251130Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135764
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461480Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727054
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Obesity due to congenital leptin deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing;in vitro | Division of Pediatric Endocrinology and Diabetes, Ulm University Medical Center | Jan 25, 2023 | The Gly59Ser variant in LEP was detected in the homozygous state in a female child of two obese Arab parents who are first-degree cousins. The variant was absent from databases including the GME Variome, Exome Variant Server (EVS) (ESP6500SI-V2), and International Genome Sample Resource (IGSR). The affected child displayed intense hyperphagia, impaired satiety, rapid weight gain, and severe early-onset obesity with high circulating leptin levels matching the clinical presentation of congenital leptin dysfunction. in vitro functional studies demonstrated that the Gly59Ser variant does not affect leptin production, leptin secretion, or leptin receptor binding, but does impair leptin receptor activation. The leptin Gly59Ser variant triggers negligible signaling engaging the leptin receptor and behaves as a competitive antagonist in the presence of non-variant leptin. According to ACMG standards and guidelines (PMID: 25741868), the Gly59Ser variant can be classified as pathogenic (PS3/PM1/PM2/PP2/PP3/PP4). Diagnostic investigations excluded Prader-Willi and Bardet-Biedl syndromes. Of note, this variant was listed in gnomAD (v2.1.1) as previously detected in the heterozygous state in a single non-Finnish European. - |
Leptin dysfunction Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 14, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of disorder (P = 0.0491);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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