rs142647085

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_002303.6(LEPR):c.2698A>G(p.Ile900Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000548 in 1,613,902 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00041 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 4 hom. )

Consequence

LEPR
NM_002303.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.29

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010891855).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000407 (62/152278) while in subpopulation SAS AF= 0.00373 (18/4820). AF 95% confidence interval is 0.00241. There are 1 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPR	NM_002303.6 linkuse as main transcript	c.2698A>G	p.Ile900Val	missense_variant	20/20	ENST00000349533.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPR	ENST00000349533.11 linkuse as main transcript	c.2698A>G	p.Ile900Val	missense_variant	20/20	1	NM_002303.6	P4	P48357-1

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00101

AC:

253

AN:

251072

Hom.:

AF XY:

0.00115

AC XY:

156

AN XY:

135716

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000521

Gnomad ASJ exome

AF:

0.00288

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00536

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000317

Gnomad OTH exome

AF:

0.000818

GnomAD4 exome

AF:

0.000563

AC:

823

AN:

1461624

Hom.:

Cov.:

AF XY:

0.000715

AC XY:

520

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00299

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00517

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000187

Gnomad4 OTH exome

AF:

0.000828

GnomAD4 genome

AF:

0.000407

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000416

Hom.:

Bravo

AF:

0.000291

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000865

AC:

105

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000655

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Monogenic Non-Syndromic Obesity

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Monogenic diabetes

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Mar 01, 2016

ACMG Criteria: PP3, BP4 -

Obesity due to leptin receptor gene deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 23, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.64

Cadd

Benign

Dann

Benign

0.81

DEOGEN2

Benign

0.095

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.56

M_CAP

Benign

0.0033

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.27

PROVEAN

Benign

0.0

REVEL

Benign

0.066

Sift

Benign

0.71

Sift4G

Benign

0.67

Polyphen

0.021

Vest4

0.064

MVP

0.30

MPC

0.088

ClinPred

0.025

GERP RS

3.4

Varity_R

0.030

gMVP

0.14

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over