rs1805094

Positions:

• chr1-65610269-G-C
• chr1-65610269-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002303.6(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 NM_002303.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.469

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]

ACMG classification

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	UniProt
LEPR	NM_002303.6	c.1968G>C	p.Lys656Asn	missense_variant	14/20	ENST00000349533.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPR	ENST00000349533.11	c.1968G>C	p.Lys656Asn	missense_variant	14/20	1	NM_002303.6	P4

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26619 AN: 151938 Hom.: 2495 Cov.: 33

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

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.: 33 AF XY: 0.167 AC XY: 121425 AN XY: 726234

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.: 33 AF XY: 0.173 AC XY: 12848 AN XY: 74330

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Obesity due to leptin receptor gene deficiency Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

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) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.41
DANN	Benign	0.92
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.56	T;.;T;T;T;.
MetaRNN	Benign	0.0019	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L;L;L;L;L
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.35	T
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	T
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

Other links and lift over

dbSNP: rs1805094; hg19: chr1-66075952; COSMIC: COSV60750073; COSMIC: COSV60750073;