rs1137100

Positions:

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. 13/20 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

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

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]

LEPR links:

LEPR (HGNC:):

LEPR links:

Genome browser will be placed here

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	Protein	UniProt
LEPR	NM_002303.6 linkuse as main transcript	c.326A>G	p.Lys109Arg	missense_variant	4/20	ENST00000349533.11	NP_002294.2	P48357-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11 linkuse as main transcript	c.326A>G	p.Lys109Arg	missense_variant	4/20	1	NM_002303.6	ENSP00000330393.7		P48357-1

Frequencies

GnomAD3 genomes

AF:

0.258

AC:

39278

AN:

152064

Hom.:

6233

Cov.:

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.:

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.:

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2018	This variant is associated with the following publications: (PMID: 24140454, 21204206, 19608021, 22228719, 20874424, 12634434, 18490929, 24549597, 25028703, 26150085, 9175732) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Obesity due to leptin receptor gene deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 21, 2021	- -

LEPTIN RECEPTOR POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jul 01, 2001

- -

Monogenic Non-Syndromic Obesity

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.083

.;.;T;.;.;.

Eigen

Benign

0.11

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.77

T;.;T;T;T;.

MetaRNN

Benign

0.0000012

T;T;T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.3

M;M;M;M;M;M

PrimateAI

Benign

0.32

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over