NM_002303.6:c.326A>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.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. 14/21 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

Publications

358 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=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 VariationId is 8523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.794 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.326A>G	p.Lys109Arg	missense	Exon 4 of 20	NP_002294.2
LEPR	NM_001003680.3		c.326A>G	p.Lys109Arg	missense	Exon 4 of 20	NP_001003680.1
LEPR	NM_001198687.2		c.326A>G	p.Lys109Arg	missense	Exon 3 of 19	NP_001185616.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LEPR	ENST00000349533.11	TSL:1 MANE Select	c.326A>G	p.Lys109Arg	missense	Exon 4 of 20	ENSP00000330393.7
LEPR	ENST00000371059.7	TSL:1	c.326A>G	p.Lys109Arg	missense	Exon 4 of 20	ENSP00000360098.3
LEPR	ENST00000344610.12	TSL:1	c.326A>G	p.Lys109Arg	missense	Exon 3 of 19	ENSP00000340884.8

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

GnomAD2 exomes

AF:

0.297

AC:

68745

AN:

231130

AF XY:

0.288

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 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

African (AFR)

AF:

0.162

AC:

5214

AN:

32232

American (AMR)

AF:

0.291

AC:

11530

AN:

39626

Ashkenazi Jewish (ASJ)

AF:

0.160

AC:

3942

AN:

24658

East Asian (EAS)

AF:

0.801

AC:

31329

AN:

39124

South Asian (SAS)

AF:

0.157

AC:

12651

AN:

80748

European-Finnish (FIN)

AF:

0.368

AC:

19355

AN:

52532

Middle Eastern (MID)

AF:

0.0972

AC:

545

AN:

5606

European-Non Finnish (NFE)

AF:

0.266

AC:

290861

AN:

1092494

Other (OTH)

AF:

0.271

AC:

15930

AN:

58718

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

13654

27309

40963

54618

68272

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10090

20180

30270

40360

50450

<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:

0.258

AC:

39292

AN:

152182

Hom.:

6237

Cov.:

AF XY:

0.263

AC XY:

19564

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.166

AC:

6896

AN:

41546

American (AMR)

AF:

0.259

AC:

3956

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.145

AC:

502

AN:

3472

East Asian (EAS)

AF:

0.814

AC:

4211

AN:

5172

South Asian (SAS)

AF:

0.173

AC:

838

AN:

4830

European-Finnish (FIN)

AF:

0.371

AC:

3919

AN:

10572

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.268

AC:

18247

AN:

67982

Other (OTH)

AF:

0.249

AC:

527

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1411

2821

4232

5642

7053

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

400

800

1200

1600

2000

<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:

0.259

Hom.:

12205

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Obesity due to leptin receptor gene deficiency (2)

LEPR POLYMORPHISM (1)

Monogenic Non-Syndromic Obesity (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.083

Eigen

Benign

0.11

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0000012

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.3

PhyloP100

2.3

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.48

REVEL

Benign

0.17

Sift

Benign

0.32

Sift4G

Benign

0.27

Polyphen

0.99

Vest4

0.026

MPC

0.093

ClinPred

0.036

GERP RS

4.5

Varity_R

0.064

gMVP

0.43

Mutation Taster

=297/3

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

Computational scores

Splicing

Publications

Other links and lift over