1-65572385-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_002303.6(LEPR):c.430G>T(p.Val144Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000368 in 1,444,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00038 ( 0 hom. )

Consequence

LEPR
NM_002303.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 0.156

Publications

3 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.030551732).

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000384 (502/1305672) while in subpopulation NFE AF = 0.000463 (468/1011082). AF 95% confidence interval is 0.000428. There are 0 homozygotes in GnomAdExome4. There are 251 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6 link	c.430G>T	p.Val144Leu	missense_variant	Exon 5 of 20	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11 link	c.430G>T	p.Val144Leu	missense_variant	Exon 5 of 20	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes

AF:

0.000216

AC:

AN:

138574

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000161

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000455

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:

0.000244

Gnomad OTH

AF:

0.00104

GnomAD2 exomes

AF:

0.000158

AC:

AN:

247206

AF XY:

0.000135

show subpopulations

Gnomad AFR exome

AF:

0.000189

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.000260

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000384

AC:

502

AN:

1305672

Hom.:

Cov.:

AF XY:

0.000387

AC XY:

251

AN XY:

647984

show subpopulations

African (AFR)

AF:

0.000105

AC:

AN:

28584

American (AMR)

AF:

0.000201

AC:

AN:

39894

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20394

East Asian (EAS)

AF:

0.00

AC:

AN:

26544

South Asian (SAS)

AF:

0.0000119

AC:

AN:

83868

European-Finnish (FIN)

AF:

0.0000994

AC:

AN:

40256

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4850

European-Non Finnish (NFE)

AF:

0.000463

AC:

468

AN:

1011082

Other (OTH)

AF:

0.000359

AC:

AN:

50200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

111

139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<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:

0.000216

AC:

AN:

138672

Hom.:

Cov.:

AF XY:

0.000136

AC XY:

AN XY:

66342

show subpopulations

African (AFR)

AF:

0.000160

AC:

AN:

37432

American (AMR)

AF:

0.000455

AC:

AN:

13198

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3372

East Asian (EAS)

AF:

0.00

AC:

AN:

4326

South Asian (SAS)

AF:

0.00

AC:

AN:

4078

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7644

Middle Eastern (MID)

AF:

0.00

AC:

AN:

252

European-Non Finnish (NFE)

AF:

0.000244

AC:

AN:

65544

Other (OTH)

AF:

0.00103

AC:

AN:

1938

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000327

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000584

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000330

EpiControl

AF:

0.000300

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

LEPR-related disorder

Uncertain:1

Jun 18, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The LEPR c.430G>T variant is predicted to result in the amino acid substitution p.Val144Leu. This variant has been reported in a patient with obesity who also carries a variant in PCSK1 (Courbage et al. 2021. PubMed ID: 34097736). This variant was observed in a cohort of individuals with obesity, and in vitro functional studies showed function similar to that of wildtype levels (Supplemental Data Set, Shah et al. 2023. PubMed ID: 36864747). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Monogenic diabetes

Uncertain:1

Nov 20, 2015

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

ACMG Criteria: BP4

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.72

CADD

Benign

6.6

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.0

.;.;T;.;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

LIST_S2

Benign

0.74

T;.;T;T;T;.

M_CAP

Benign

0.0059

MetaRNN

Benign

0.031

T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.55

N;N;N;N;N;N

PhyloP100

0.16

PrimateAI

Benign

0.26

PROVEAN

Benign

0.15

N;N;N;N;.;N

Sift

Benign

0.99

T;T;T;T;.;T

Sift4G

Benign

1.0

T;T;T;T;T;T

Vest4

0.066

ClinPred

0.0073

GERP RS

-5.3

Varity_R

0.036

gMVP

0.44

Mutation Taster

=98/2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over