rs1137101

chr1-65592830-A-Gchr1-65592830-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.668A>G(p.Gln223Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 1,612,512 control chromosomes in the GnomAD database, including 183,943 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (20073 hom., cov: 31)
  • Exomes 𝑓: 0.47 (163870 hom.)
• Consequence: LEPR NM_002303.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.89

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=7.772684E-7).
• BP6: Variant 1-65592830-A-G is Benign according to our data. Variant chr1-65592830-A-G is described in ClinVar as [Benign]. Clinvar id is 8521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-65592830-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPR	NM_002303.6	c.668A>G	p.Gln223Arg	missense_variant	6/20	ENST00000349533.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPR	ENST00000349533.11	c.668A>G	p.Gln223Arg	missense_variant	6/20	1	NM_002303.6	P4

Frequencies

GnomAD3 genomes AF: 0.503 AC: 76329 AN: 151632 Hom.: 20042 Cov.: 31

Gnomad AFR AF: 0.556

Gnomad AMI AF: 0.272

Gnomad AMR AF: 0.441

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.879

Gnomad SAS AF: 0.491

Gnomad FIN AF: 0.594

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.470

GnomAD3 exomes AF: 0.506 AC: 126767 AN: 250536 Hom.: 33913 AF XY: 0.499 AC XY: 67578 AN XY: 135420

Gnomad AFR exome AF: 0.562

Gnomad AMR exome AF: 0.456

Gnomad ASJ exome AF: 0.427

Gnomad EAS exome AF: 0.881

Gnomad SAS exome AF: 0.473

Gnomad FIN exome AF: 0.598

Gnomad NFE exome AF: 0.452

Gnomad OTH exome AF: 0.472

GnomAD4 exome AF: 0.466 AC: 680577 AN: 1460762 Hom.: 163870 Cov.: 62 AF XY: 0.464 AC XY: 337258 AN XY: 726694

Gnomad4 AFR exome AF: 0.559

Gnomad4 AMR exome AF: 0.454

Gnomad4 ASJ exome AF: 0.424

Gnomad4 EAS exome AF: 0.873

Gnomad4 SAS exome AF: 0.473

Gnomad4 FIN exome AF: 0.600

Gnomad4 NFE exome AF: 0.443

Gnomad4 OTH exome AF: 0.477

GnomAD4 genome AF: 0.504 AC: 76408 AN: 151750 Hom.: 20073 Cov.: 31 AF XY: 0.510 AC XY: 37793 AN XY: 74150

Gnomad4 AFR AF: 0.557

Gnomad4 AMR AF: 0.441

Gnomad4 ASJ AF: 0.419

Gnomad4 EAS AF: 0.878

Gnomad4 SAS AF: 0.489

Gnomad4 FIN AF: 0.594

Gnomad4 NFE AF: 0.453

Gnomad4 OTH AF: 0.476

Alfa AF: 0.458 Hom.: 38572

Bravo AF: 0.494

ESP6500AA AF: 0.561 AC: 2471

ESP6500EA AF: 0.454 AC: 3906

ExAC AF: 0.509 AC: 61850

Asia WGS AF: 0.680 AC: 2362 AN: 3478

EpiCase AF: 0.429

EpiControl AF: 0.425

ClinVar

Significance: Benign

Submissions summary: Benign:8

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, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2018	This variant is associated with the following publications: (PMID: 9175732, 26150085, 24985001, 32429577, 24051404, 23954230, 23429533, 12634434, 28386678, 22333091, 25114924, 24631298, 11354636, 24146750, 24743494, 21233812, 18997673, 20874424, 19344216, 21698367, 25516614, 18204169, 22127368, 18855010, 21393862, 21207066, 20183928, 22734460, 23769971, 19017403, 21159927, 23026206, 23966608, 19427969) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

LEPTIN RECEPTOR POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Nov 01, 2007

- -

Monogenic Non-Syndromic Obesity Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Obesity due to leptin receptor gene deficiency 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	0.099
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Uncertain	0.99
Eigen	Benign	-0.094
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.53	T;.;T;T;T;.
MetaRNN	Benign	7.8e-7	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L;L;L;L;L
MutationTaster	Benign	0.62	P;P;P;P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N;N;N;N;.;N
REVEL	Benign	0.034
Sift	Benign	0.22	T;T;T;T;.;T
Sift4G	Benign	0.19	T;T;T;T;T;T
Polyphen		0.83	P;B;B;.;B;.
Vest4		0.082
MPC		0.12
ClinPred		0.0063	T
GERP RS		3.7
Varity_R		0.14
gMVP		0.49

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: rs1137101; hg19: chr1-66058513; COSMIC: COSV60756706;