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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 0.503 in 151632 control chromosomes in the gnomAD Genomes database, including 20042 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 (β˜…β˜…).

Frequency

Genomes: 𝑓 0.50 ( 20042 hom., cov: 31)
Exomes 𝑓: 0.51 ( 33913 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

Links

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
?
GnomAd 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
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
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, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, criteria provided, single submitterclinical testingAthena Diagnostics IncJul 26, 2017- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeNov 01, 2022- -
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) -
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
19
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;