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GeneBe

rs1137101

Variant summary

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

The NM_002303.6(LEPR):c.668A>G(p.Gln223Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 1,612,512 control chromosomes in the GnomAD database, including 183,943 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.50 ( 20073 hom., cov: 31)
Exomes 𝑓: 0.47 ( 163870 hom. )

Consequence

LEPR
NM_002303.6 missense

Scores

2
15

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.89
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=7.772684E-7).
BP6
Variant 1-65592830-A-G is Benign according to our data. Variant chr1-65592830-A-G is described in ClinVar as [Benign]. Clinvar id is 8521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-65592830-A-G is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.857 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LEPRNM_002303.6 linkuse as main transcriptc.668A>G p.Gln223Arg missense_variant 6/20 ENST00000349533.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LEPRENST00000349533.11 linkuse as main transcriptc.668A>G p.Gln223Arg missense_variant 6/201 NM_002303.6 P4P48357-1

Frequencies

GnomAD3 genomes
AF:
0.503
AC:
76329
AN:
151632
Hom.:
20042
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.556
Gnomad AMI
AF:
0.272
Gnomad AMR
AF:
0.441
Gnomad ASJ
AF:
0.419
Gnomad EAS
AF:
0.879
Gnomad SAS
AF:
0.491
Gnomad FIN
AF:
0.594
Gnomad MID
AF:
0.339
Gnomad NFE
AF:
0.453
Gnomad OTH
AF:
0.470
GnomAD3 exomes
AF:
0.506
AC:
126767
AN:
250536
Hom.:
33913
AF XY:
0.499
AC XY:
67578
AN XY:
135420
show subpopulations
Gnomad AFR exome
AF:
0.562
Gnomad AMR exome
AF:
0.456
Gnomad ASJ exome
AF:
0.427
Gnomad EAS exome
AF:
0.881
Gnomad SAS exome
AF:
0.473
Gnomad FIN exome
AF:
0.598
Gnomad NFE exome
AF:
0.452
Gnomad OTH exome
AF:
0.472
GnomAD4 exome
AF:
0.466
AC:
680577
AN:
1460762
Hom.:
163870
Cov.:
62
AF XY:
0.464
AC XY:
337258
AN XY:
726694
show subpopulations
Gnomad4 AFR exome
AF:
0.559
Gnomad4 AMR exome
AF:
0.454
Gnomad4 ASJ exome
AF:
0.424
Gnomad4 EAS exome
AF:
0.873
Gnomad4 SAS exome
AF:
0.473
Gnomad4 FIN exome
AF:
0.600
Gnomad4 NFE exome
AF:
0.443
Gnomad4 OTH exome
AF:
0.477
GnomAD4 genome
AF:
0.504
AC:
76408
AN:
151750
Hom.:
20073
Cov.:
31
AF XY:
0.510
AC XY:
37793
AN XY:
74150
show subpopulations
Gnomad4 AFR
AF:
0.557
Gnomad4 AMR
AF:
0.441
Gnomad4 ASJ
AF:
0.419
Gnomad4 EAS
AF:
0.878
Gnomad4 SAS
AF:
0.489
Gnomad4 FIN
AF:
0.594
Gnomad4 NFE
AF:
0.453
Gnomad4 OTH
AF:
0.476
Alfa
AF:
0.458
Hom.:
38572
Bravo
AF:
0.494
ESP6500AA
AF:
0.561
AC:
2471
ESP6500EA
AF:
0.454
AC:
3906
ExAC
AF:
0.509
AC:
61850
Asia WGS
AF:
0.680
AC:
2362
AN:
3478
EpiCase
AF:
0.429
EpiControl
AF:
0.425

ClinVar

Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsJul 26, 2017- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxAug 09, 2018This variant is associated with the following publications: (PMID: 9175732, 26150085, 24985001, 32429577, 24051404, 23954230, 23429533, 12634434, 28386678, 22333091, 25114924, 24631298, 11354636, 24146750, 24743494, 21233812, 18997673, 20874424, 19344216, 21698367, 25516614, 18204169, 22127368, 18855010, 21393862, 21207066, 20183928, 22734460, 23769971, 19017403, 21159927, 23026206, 23966608, 19427969) -
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
LEPTIN RECEPTOR POLYMORPHISM Benign:1
Benign, no assertion criteria providedliterature onlyOMIMNov 01, 2007- -
Monogenic Non-Syndromic Obesity Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Obesity due to leptin receptor gene deficiency 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
0.099
BayesDel_addAF
Benign
-0.56
T
BayesDel_noAF
Benign
-0.44
Cadd
Benign
16
Dann
Uncertain
0.99
Eigen
Benign
-0.094
Eigen_PC
Benign
0.016
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.53
T;.;T;T;T;.
MetaRNN
Benign
7.8e-7
T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.9
L;L;L;L;L;L
MutationTaster
Benign
0.62
P;P;P;P;P;P
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-1.4
N;N;N;N;.;N
REVEL
Benign
0.034
Sift
Benign
0.22
T;T;T;T;.;T
Sift4G
Benign
0.19
T;T;T;T;T;T
Polyphen
0.83
P;B;B;.;B;.
Vest4
0.082
MPC
0.12
ClinPred
0.0063
T
GERP RS
3.7
Varity_R
0.14
gMVP
0.49

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: rs1137101; hg19: chr1-66058513; COSMIC: COSV60756706; API