chr1-65610269-G-C

Position:

chr1-65610269-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000349533.11(LEPR):c.1968G>C(p.Lys656Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,611,922 control chromosomes in the GnomAD database, including 23,611 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

Frequency

Genomes: 𝑓 0.18 ( 2494 hom., cov: 33)

Exomes 𝑓: 0.17 ( 21117 hom. )

Consequence

LEPR
ENST00000349533.11 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.469

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019337535).

BP6

Variant 1-65610269-G-C is Benign according to our data. Variant chr1-65610269-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 8524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-65610269-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LEPR	NM_002303.6 linkuse as main transcript	c.1968G>C	p.Lys656Asn	missense_variant	14/20	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11 linkuse as main transcript	c.1968G>C	p.Lys656Asn	missense_variant	14/20	1	NM_002303.6	ENSP00000330393	P4	P48357-1

Frequencies

GnomAD3 genomes

AF:

0.175

AC:

26619

AN:

151938

Hom.:

2495

Cov.:

show subpopulations

Gnomad AFR

AF:

0.195

Gnomad AMI

AF:

0.237

Gnomad AMR

AF:

0.204

Gnomad ASJ

AF:

0.221

Gnomad EAS

AF:

0.0563

Gnomad SAS

AF:

0.126

Gnomad FIN

AF:

0.126

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.174

Gnomad OTH

AF:

0.179

GnomAD3 exomes

AF:

0.159

AC:

39679

AN:

250258

Hom.:

3351

AF XY:

0.160

AC XY:

21636

AN XY:

135428

show subpopulations

Gnomad AFR exome

AF:

0.194

Gnomad AMR exome

AF:

0.167

Gnomad ASJ exome

AF:

0.210

Gnomad EAS exome

AF:

0.0522

Gnomad SAS exome

AF:

0.141

Gnomad FIN exome

AF:

0.123

Gnomad NFE exome

AF:

0.174

Gnomad OTH exome

AF:

0.178

GnomAD4 exome

AF:

0.167

AC:

243993

AN:

1459864

Hom.:

21117

Cov.:

AF XY:

0.167

AC XY:

121425

AN XY:

726234

show subpopulations

Gnomad4 AFR exome

AF:

0.194

Gnomad4 AMR exome

AF:

0.170

Gnomad4 ASJ exome

AF:

0.216

Gnomad4 EAS exome

AF:

0.0779

Gnomad4 SAS exome

AF:

0.143

Gnomad4 FIN exome

AF:

0.123

Gnomad4 NFE exome

AF:

0.172

Gnomad4 OTH exome

AF:

0.168

GnomAD4 genome

AF:

0.175

AC:

26632

AN:

152058

Hom.:

2494

Cov.:

AF XY:

0.173

AC XY:

12848

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.194

Gnomad4 AMR

AF:

0.203

Gnomad4 ASJ

AF:

0.221

Gnomad4 EAS

AF:

0.0566

Gnomad4 SAS

AF:

0.127

Gnomad4 FIN

AF:

0.126

Gnomad4 NFE

AF:

0.174

Gnomad4 OTH

AF:

0.176

Alfa

AF:

0.146

Hom.:

633

Bravo

AF:

0.179

TwinsUK

AF:

0.180

AC:

668

ALSPAC

AF:

0.164

AC:

633

ESP6500AA

AF:

0.188

AC:

828

ESP6500EA

AF:

0.171

AC:

1467

ExAC

AF:

0.158

AC:

19136

Asia WGS

AF:

0.0970

AC:

336

AN:

3478

EpiCase

AF:

0.193

EpiControl

AF:

0.194

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2018	This variant is associated with the following publications: (PMID: 20814201, 22530350, 23315873, 23266707, 18413223, 14970363, 20185531, 12006639, 9175732) -

Obesity due to leptin receptor gene deficiency

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 19, 2017	- -

LEPTIN RECEPTOR POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jul 01, 2001

- -

Monogenic Non-Syndromic Obesity

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.41

DANN

Benign

0.92

DEOGEN2

Benign

0.081

.;.;T;.;.;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.56

T;.;T;T;T;.

MetaRNN

Benign

0.0019

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L;L;L;L;L

MutationTaster

Benign

1.0

P;P;P;P;P;P

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.12

N;N;N;N;.;N

REVEL

Benign

0.12

Sift

Benign

0.45

T;T;T;T;.;T

Sift4G

Benign

0.10

T;T;T;T;T;T

Polyphen

0.94

P;P;P;.;P;.

Vest4

0.030

MutPred

0.16

Loss of methylation at K656 (P = 0.0183);Loss of methylation at K656 (P = 0.0183);Loss of methylation at K656 (P = 0.0183);Loss of methylation at K656 (P = 0.0183);Loss of methylation at K656 (P = 0.0183);Loss of methylation at K656 (P = 0.0183);

MPC

0.14

ClinPred

0.0037

GERP RS

-2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.061

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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