1-65592830-A-G

Position:

chr1-65592830-A-G

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. 14/20 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

Clinical Significance

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

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]

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=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	Protein	UniProt
LEPR	NM_002303.6 linkuse as main transcript	c.668A>G	p.Gln223Arg	missense_variant	6/20	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11 linkuse as main transcript	c.668A>G	p.Gln223Arg	missense_variant	6/20	1	NM_002303.6	ENSP00000330393	P4	P48357-1

Frequencies

GnomAD3 genomes

AF:

0.503

AC:

76329

AN:

151632

Hom.:

20042

Cov.:

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.:

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.:

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2018	This 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 submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

LEPTIN RECEPTOR POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Nov 01, 2007

- -

Monogenic Non-Syndromic Obesity

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Obesity due to leptin receptor gene deficiency

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

0.099

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

.;.;T;.;.;.

Eigen

Benign

-0.094

Eigen_PC

Benign

0.016

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.53

T;.;T;T;T;.

MetaRNN

Benign

7.8e-7

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;L;L;L;L;L

MutationTaster

Benign

0.62

P;P;P;P;P;P

PrimateAI

Benign

0.28

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

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.

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