Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000349533.11(LEPR):c.2096C>T(p.Thr699Met) variant causes a missense change. The variant allele was found at a frequency of 0.00174 in 1,614,158 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0096 ( 20 hom., cov: 32)

Exomes 𝑓: 0.00092 ( 22 hom. )

Consequence

LEPR
ENST00000349533.11 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 5.52

Publications

11 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=0.0063533783).

BP6

Variant 1-65616108-C-T is Benign according to our data. Variant chr1-65616108-C-T is described in ClinVar as Benign. ClinVar VariationId is 393364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00961 (1464/152308) while in subpopulation AFR AF = 0.0338 (1404/41566). AF 95% confidence interval is 0.0323. There are 20 homozygotes in GnomAd4. There are 703 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 20 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000349533.11. 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.2096C>T	p.Thr699Met	missense	Exon 15 of 20	NP_002294.2
LEPR	NM_001003680.3		c.2096C>T	p.Thr699Met	missense	Exon 15 of 20	NP_001003680.1
LEPR	NM_001198687.2		c.2096C>T	p.Thr699Met	missense	Exon 14 of 19	NP_001185616.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LEPR	ENST00000349533.11	TSL:1 MANE Select	c.2096C>T	p.Thr699Met	missense	Exon 15 of 20	ENSP00000330393.7
LEPR	ENST00000371059.7	TSL:1	c.2096C>T	p.Thr699Met	missense	Exon 15 of 20	ENSP00000360098.3
LEPR	ENST00000344610.12	TSL:1	c.2096C>T	p.Thr699Met	missense	Exon 14 of 19	ENSP00000340884.8

Frequencies

GnomAD3 genomes

AF:

0.00961

AC:

1463

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0339

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00294

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00251

AC:

632

AN:

251406

AF XY:

0.00197

show subpopulations

Gnomad AFR exome

AF:

0.0354

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.000920

AC:

1345

AN:

1461850

Hom.:

Cov.:

AF XY:

0.000777

AC XY:

565

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.0333

AC:

1114

AN:

33478

American (AMR)

AF:

0.00139

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000387

AC:

AN:

1111992

Other (OTH)

AF:

0.00187

AC:

113

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

187

281

374

468

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.00961

AC:

1464

AN:

152308

Hom.:

Cov.:

AF XY:

0.00944

AC XY:

703

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0338

AC:

1404

AN:

41566

American (AMR)

AF:

0.00294

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68024

Other (OTH)

AF:

0.00568

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

155

233

310

388

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00362

Hom.:

Bravo

AF:

0.0114

ESP6500AA

AF:

0.0377

AC:

166

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00320

AC:

388

Asia WGS

AF:

0.00115

AC:

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 (4)

Monogenic diabetes (1)

not specified (1)

Obesity due to leptin receptor gene deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0064

MetaSVM

Benign

-0.41

MutationAssessor

Pathogenic

2.9

PhyloP100

5.5

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.27

Sift

Uncertain

0.0030

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.85

MVP

0.66

MPC

0.54

ClinPred

0.027

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.31

gMVP

0.61

Mutation Taster

=69/31

polymorphism

(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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over