chr1-65592830-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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

Publications

706 publications found

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 Gene-Disease associations (from GenCC):

obesity due to leptin receptor gene deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

LEPR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 8521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.857 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002303.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LEPR	NM_002303.6	MANE Select	c.668A>G	p.Gln223Arg	missense	Exon 6 of 20	NP_002294.2
LEPR	NM_001003680.3		c.668A>G	p.Gln223Arg	missense	Exon 6 of 20	NP_001003680.1
LEPR	NM_001198687.2		c.668A>G	p.Gln223Arg	missense	Exon 5 of 19	NP_001185616.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LEPR	ENST00000349533.11	TSL:1 MANE Select	c.668A>G	p.Gln223Arg	missense	Exon 6 of 20	ENSP00000330393.7
LEPR	ENST00000371059.7	TSL:1	c.668A>G	p.Gln223Arg	missense	Exon 6 of 20	ENSP00000360098.3
LEPR	ENST00000344610.12	TSL:1	c.668A>G	p.Gln223Arg	missense	Exon 5 of 19	ENSP00000340884.8

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

GnomAD2 exomes

AF:

0.506

AC:

126767

AN:

250536

AF XY:

0.499

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 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

African (AFR)

AF:

0.559

AC:

18687

AN:

33444

American (AMR)

AF:

0.454

AC:

20267

AN:

44618

Ashkenazi Jewish (ASJ)

AF:

0.424

AC:

11062

AN:

26070

East Asian (EAS)

AF:

0.873

AC:

34667

AN:

39688

South Asian (SAS)

AF:

0.473

AC:

40745

AN:

86228

European-Finnish (FIN)

AF:

0.600

AC:

32029

AN:

53382

Middle Eastern (MID)

AF:

0.286

AC:

1647

AN:

5762

European-Non Finnish (NFE)

AF:

0.443

AC:

492712

AN:

1111242

Other (OTH)

AF:

0.477

AC:

28761

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

21448

42896

64344

85792

107240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15090

30180

45270

60360

75450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.504

AC:

76408

AN:

151750

Hom.:

20073

Cov.:

AF XY:

0.510

AC XY:

37793

AN XY:

74150

show subpopulations

African (AFR)

AF:

0.557

AC:

23024

AN:

41370

American (AMR)

AF:

0.441

AC:

6720

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.419

AC:

1451

AN:

3464

East Asian (EAS)

AF:

0.878

AC:

4528

AN:

5156

South Asian (SAS)

AF:

0.489

AC:

2349

AN:

4804

European-Finnish (FIN)

AF:

0.594

AC:

6271

AN:

10552

Middle Eastern (MID)

AF:

0.347

AC:

102

AN:

294

European-Non Finnish (NFE)

AF:

0.453

AC:

30713

AN:

67860

Other (OTH)

AF:

0.476

AC:

1002

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1843

3687

5530

7374

9217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

680

1360

2040

2720

3400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.466

Hom.:

76076

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

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 26, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:3

Aug 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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)

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Monogenic Non-Syndromic Obesity

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LEPR POLYMORPHISM

Benign:1

Nov 01, 2007

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

Obesity due to leptin receptor gene deficiency

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Benign

-0.094

Eigen_PC

Benign

0.016

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.53

MetaRNN

Benign

7.8e-7

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

2.9

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.4

REVEL

Benign

0.034

Sift

Benign

0.22

Sift4G

Benign

0.19

Polyphen

0.83

Vest4

0.082

MPC

0.12

ClinPred

0.0063

GERP RS

3.7

Varity_R

0.14

gMVP

0.49

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over