rs1805134

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002303.6(LEPR):c.1029T>C(p.Ser343Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,612,898 control chromosomes in the GnomAD database, including 38,903 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 4919 hom., cov: 32)

Exomes 𝑓: 0.21 ( 33984 hom. )

Consequence

LEPR
NM_002303.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.467

Publications

50 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 1-65601426-T-C is Benign according to our data. Variant chr1-65601426-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 297991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.467 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6 link	c.1029T>C	p.Ser343Ser	synonymous_variant	Exon 9 of 20	ENST00000349533.11	NP_002294.2	P48357-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11 link	c.1029T>C	p.Ser343Ser	synonymous_variant	Exon 9 of 20	1	NM_002303.6	ENSP00000330393.7		P48357-1

Frequencies

GnomAD3 genomes

AF:

0.237

AC:

36024

AN:

151820

Hom.:

4909

Cov.:

show subpopulations

Gnomad AFR

AF:

0.329

Gnomad AMI

AF:

0.109

Gnomad AMR

AF:

0.170

Gnomad ASJ

AF:

0.317

Gnomad EAS

AF:

0.0670

Gnomad SAS

AF:

0.343

Gnomad FIN

AF:

0.215

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.204

Gnomad OTH

AF:

0.224

GnomAD2 exomes

AF:

0.217

AC:

54505

AN:

250920

AF XY:

0.224

show subpopulations

Gnomad AFR exome

AF:

0.339

Gnomad AMR exome

AF:

0.124

Gnomad ASJ exome

AF:

0.300

Gnomad EAS exome

AF:

0.0596

Gnomad FIN exome

AF:

0.226

Gnomad NFE exome

AF:

0.211

Gnomad OTH exome

AF:

0.226

GnomAD4 exome

AF:

0.208

AC:

304579

AN:

1460960

Hom.:

33984

Cov.:

AF XY:

0.213

AC XY:

154954

AN XY:

726782

show subpopulations

African (AFR)

AF:

0.333

AC:

11145

AN:

33458

American (AMR)

AF:

0.133

AC:

5947

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.300

AC:

7827

AN:

26122

East Asian (EAS)

AF:

0.0855

AC:

3389

AN:

39650

South Asian (SAS)

AF:

0.338

AC:

29138

AN:

86220

European-Finnish (FIN)

AF:

0.227

AC:

12081

AN:

53238

Middle Eastern (MID)

AF:

0.205

AC:

1168

AN:

5708

European-Non Finnish (NFE)

AF:

0.198

AC:

220608

AN:

1111494

Other (OTH)

AF:

0.220

AC:

13276

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

13226

26452

39678

52904

66130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7722

15444

23166

30888

38610

<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:

0.237

AC:

36077

AN:

151938

Hom.:

4919

Cov.:

AF XY:

0.237

AC XY:

17597

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.329

AC:

13649

AN:

41462

American (AMR)

AF:

0.170

AC:

2598

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.317

AC:

1097

AN:

3464

East Asian (EAS)

AF:

0.0670

AC:

347

AN:

5182

South Asian (SAS)

AF:

0.342

AC:

1648

AN:

4822

European-Finnish (FIN)

AF:

0.215

AC:

2276

AN:

10584

Middle Eastern (MID)

AF:

0.252

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.204

AC:

13812

AN:

67862

Other (OTH)

AF:

0.226

AC:

477

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1372

2744

4116

5488

6860

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

382

764

1146

1528

1910

<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:

0.217

Hom.:

6902

Bravo

AF:

0.232

Asia WGS

AF:

0.275

AC:

955

AN:

3478

EpiCase

AF:

0.209

EpiControl

AF:

0.207

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Dec 07, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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, 11380591, 12646666) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

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

- -

Monogenic Non-Syndromic Obesity

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Obesity due to leptin receptor gene deficiency

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

5.8

(source)

DANN

Benign

0.63

PhyloP100

0.47

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over