rs1137100

chr1-65570758-A-Gchr1-65570758-A-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.326A>G(p.Lys109Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 1,577,920 control chromosomes in the GnomAD database, including 67,595 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6237 hom., cov: 33)
  • Exomes 𝑓: 0.27 (61358 hom.)
• Consequence: LEPR NM_002303.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.35

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=1.2246074E-6).
• BP6: Variant 1-65570758-A-G is Benign according to our data. Variant chr1-65570758-A-G is described in ClinVar as [Benign]. Clinvar id is 8523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-65570758-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.794 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPR	NM_002303.6	c.326A>G	p.Lys109Arg	missense_variant	4/20	ENST00000349533.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPR	ENST00000349533.11	c.326A>G	p.Lys109Arg	missense_variant	4/20	1	NM_002303.6	P4

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39278 AN: 152064 Hom.: 6233 Cov.: 33

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.814

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.371

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.268

Gnomad OTH AF: 0.245

GnomAD3 exomes AF: 0.297 AC: 68745 AN: 231130 Hom.: 13425 AF XY: 0.288 AC XY: 35966 AN XY: 124718

Gnomad AFR exome AF: 0.163

Gnomad AMR exome AF: 0.307

Gnomad ASJ exome AF: 0.164

Gnomad EAS exome AF: 0.824

Gnomad SAS exome AF: 0.157

Gnomad FIN exome AF: 0.369

Gnomad NFE exome AF: 0.259

Gnomad OTH exome AF: 0.263

GnomAD4 exome AF: 0.274 AC: 391357 AN: 1425738 Hom.: 61358 Cov.: 33 AF XY: 0.269 AC XY: 189426 AN XY: 704476

Gnomad4 AFR exome AF: 0.162

Gnomad4 AMR exome AF: 0.291

Gnomad4 ASJ exome AF: 0.160

Gnomad4 EAS exome AF: 0.801

Gnomad4 SAS exome AF: 0.157

Gnomad4 FIN exome AF: 0.368

Gnomad4 NFE exome AF: 0.266

Gnomad4 OTH exome AF: 0.271

GnomAD4 genome AF: 0.258 AC: 39292 AN: 152182 Hom.: 6237 Cov.: 33 AF XY: 0.263 AC XY: 19564 AN XY: 74388

Gnomad4 AFR AF: 0.166

Gnomad4 AMR AF: 0.259

Gnomad4 ASJ AF: 0.145

Gnomad4 EAS AF: 0.814

Gnomad4 SAS AF: 0.173

Gnomad4 FIN AF: 0.371

Gnomad4 NFE AF: 0.268

Gnomad4 OTH AF: 0.249

Alfa AF: 0.263 Hom.: 9312

Bravo AF: 0.250

TwinsUK AF: 0.272 AC: 1008

ALSPAC AF: 0.272 AC: 1050

ESP6500AA AF: 0.173 AC: 762

ESP6500EA AF: 0.264 AC: 2273

ExAC AF: 0.285 AC: 34659

Asia WGS AF: 0.414 AC: 1437 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 28, 2017	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2018	This variant is associated with the following publications: (PMID: 24140454, 21204206, 19608021, 22228719, 20874424, 12634434, 18490929, 24549597, 25028703, 26150085, 9175732) -

Obesity due to leptin receptor gene deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 21, 2021	- -

LEPTIN RECEPTOR POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jul 01, 2001

- -

Monogenic Non-Syndromic Obesity Benign:1

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	0.087
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Uncertain	0.99
Eigen	Benign	0.11
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.77	T;.;T;T;T;.
MetaRNN	Benign	0.0000012	T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.3	M;M;M;M;M;M
MutationTaster	Benign	0.69	P;P;P;P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.48	N;N;N;N;.;N
REVEL	Benign	0.17
Sift	Benign	0.32	T;T;T;T;.;T
Sift4G	Benign	0.27	T;T;T;T;T;T
Polyphen		0.99	D;B;B;D;B;D
Vest4		0.026
MPC		0.093
ClinPred		0.036	T
GERP RS		4.5
Varity_R		0.064
gMVP		0.43

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

Other links and lift over

dbSNP: rs1137100; hg19: chr1-66036441;