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GeneBe

rs1137100

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002303.6(LEPR):c.326A>G(p.Lys109Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 1,577,920 control chromosomes in the GnomAD database, including 67,595 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 6237 hom., cov: 33)
Exomes 𝑓: 0.27 ( 61358 hom. )

Consequence

LEPR
NM_002303.6 missense

Scores

3
14

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.35
Variant links:
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 -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=1.2246074E-6).
BP6
Variant 1-65570758-A-G is Benign according to our data. Variant chr1-65570758-A-G is described in ClinVar as [Benign]. Clinvar id is 8523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-65570758-A-G is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.794 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LEPRNM_002303.6 linkuse as main transcriptc.326A>G p.Lys109Arg missense_variant 4/20 ENST00000349533.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LEPRENST00000349533.11 linkuse as main transcriptc.326A>G p.Lys109Arg missense_variant 4/201 NM_002303.6 P4P48357-1

Frequencies

GnomAD3 genomes
AF:
0.258
AC:
39278
AN:
152064
Hom.:
6233
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.166
Gnomad AMI
AF:
0.183
Gnomad AMR
AF:
0.258
Gnomad ASJ
AF:
0.145
Gnomad EAS
AF:
0.814
Gnomad SAS
AF:
0.173
Gnomad FIN
AF:
0.371
Gnomad MID
AF:
0.0981
Gnomad NFE
AF:
0.268
Gnomad OTH
AF:
0.245
GnomAD3 exomes
AF:
0.297
AC:
68745
AN:
231130
Hom.:
13425
AF XY:
0.288
AC XY:
35966
AN XY:
124718
show subpopulations
Gnomad AFR exome
AF:
0.163
Gnomad AMR exome
AF:
0.307
Gnomad ASJ exome
AF:
0.164
Gnomad EAS exome
AF:
0.824
Gnomad SAS exome
AF:
0.157
Gnomad FIN exome
AF:
0.369
Gnomad NFE exome
AF:
0.259
Gnomad OTH exome
AF:
0.263
GnomAD4 exome
AF:
0.274
AC:
391357
AN:
1425738
Hom.:
61358
Cov.:
33
AF XY:
0.269
AC XY:
189426
AN XY:
704476
show subpopulations
Gnomad4 AFR exome
AF:
0.162
Gnomad4 AMR exome
AF:
0.291
Gnomad4 ASJ exome
AF:
0.160
Gnomad4 EAS exome
AF:
0.801
Gnomad4 SAS exome
AF:
0.157
Gnomad4 FIN exome
AF:
0.368
Gnomad4 NFE exome
AF:
0.266
Gnomad4 OTH exome
AF:
0.271
GnomAD4 genome
AF:
0.258
AC:
39292
AN:
152182
Hom.:
6237
Cov.:
33
AF XY:
0.263
AC XY:
19564
AN XY:
74388
show subpopulations
Gnomad4 AFR
AF:
0.166
Gnomad4 AMR
AF:
0.259
Gnomad4 ASJ
AF:
0.145
Gnomad4 EAS
AF:
0.814
Gnomad4 SAS
AF:
0.173
Gnomad4 FIN
AF:
0.371
Gnomad4 NFE
AF:
0.268
Gnomad4 OTH
AF:
0.249
Alfa
AF:
0.263
Hom.:
9312
Bravo
AF:
0.250
TwinsUK
AF:
0.272
AC:
1008
ALSPAC
AF:
0.272
AC:
1050
ESP6500AA
AF:
0.173
AC:
762
ESP6500EA
AF:
0.264
AC:
2273
ExAC
AF:
0.285
AC:
34659
Asia WGS
AF:
0.414
AC:
1437
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, criteria provided, single submitterclinical testingAthena Diagnostics IncJul 28, 2017- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxOct 22, 2018This variant is associated with the following publications: (PMID: 24140454, 21204206, 19608021, 22228719, 20874424, 12634434, 18490929, 24549597, 25028703, 26150085, 9175732) -
Obesity due to leptin receptor gene deficiency Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJul 21, 2021- -
LEPTIN RECEPTOR POLYMORPHISM Benign:1
Benign, no assertion criteria providedliterature onlyOMIMJul 01, 2001- -
Monogenic Non-Syndromic Obesity Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.087
BayesDel_addAF
Benign
-0.64
T
BayesDel_noAF
Benign
-0.55
Cadd
Benign
16
Dann
Uncertain
0.99
Eigen
Benign
0.11
Eigen_PC
Benign
0.19
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.77
T;.;T;T;T;.
MetaRNN
Benign
0.0000012
T;T;T;T;T;T
MetaSVM
Benign
-0.89
T
MutationAssessor
Uncertain
2.3
M;M;M;M;M;M
MutationTaster
Benign
0.69
P;P;P;P;P;P
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-0.48
N;N;N;N;.;N
REVEL
Benign
0.17
Sift
Benign
0.32
T;T;T;T;.;T
Sift4G
Benign
0.27
T;T;T;T;T;T
Polyphen
0.99
D;B;B;D;B;D
Vest4
0.026
MPC
0.093
ClinPred
0.036
T
GERP RS
4.5
Varity_R
0.064
gMVP
0.43

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1137100; hg19: chr1-66036441; API