1-65636574-G-A

Position:

• chr1-65636574-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002303.6(LEPR):​c.3057G>A​(p.Pro1019=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 1,613,714 control chromosomes in the GnomAD database, including 139,816 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15242 hom., cov: 32)
  • Exomes 𝑓: 0.40 (124574 hom.)
• Consequence: LEPR NM_002303.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.823

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 1-65636574-G-A is Benign according to our data. Variant chr1-65636574-G-A is described in ClinVar as [Benign]. Clinvar id is 298000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-65636574-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.823 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.849 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPR	NM_002303.6	c.3057G>A	p.Pro1019=	synonymous_variant	20/20	ENST00000349533.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPR	ENST00000349533.11	c.3057G>A	p.Pro1019=	synonymous_variant	20/20	1	NM_002303.6	P4

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66340 AN: 151842 Hom.: 15210 Cov.: 32

Gnomad AFR AF: 0.451

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.376

Gnomad EAS AF: 0.870

Gnomad SAS AF: 0.464

Gnomad FIN AF: 0.496

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.382

Gnomad OTH AF: 0.416

GnomAD3 exomes AF: 0.457 AC: 114099 AN: 249416 Hom.: 28262 AF XY: 0.452 AC XY: 61090 AN XY: 135292

Gnomad AFR exome AF: 0.453

Gnomad AMR exome AF: 0.507

Gnomad ASJ exome AF: 0.374

Gnomad EAS exome AF: 0.873

Gnomad SAS exome AF: 0.466

Gnomad FIN exome AF: 0.484

Gnomad NFE exome AF: 0.377

Gnomad OTH exome AF: 0.425

GnomAD4 exome AF: 0.403 AC: 589205 AN: 1461754 Hom.: 124574 Cov.: 69 AF XY: 0.404 AC XY: 293419 AN XY: 727172

Gnomad4 AFR exome AF: 0.453

Gnomad4 AMR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.381

Gnomad4 EAS exome AF: 0.868

Gnomad4 SAS exome AF: 0.464

Gnomad4 FIN exome AF: 0.479

Gnomad4 NFE exome AF: 0.373

Gnomad4 OTH exome AF: 0.414

GnomAD4 genome AF: 0.437 AC: 66434 AN: 151960 Hom.: 15242 Cov.: 32 AF XY: 0.446 AC XY: 33101 AN XY: 74280

Gnomad4 AFR AF: 0.451

Gnomad4 AMR AF: 0.472

Gnomad4 ASJ AF: 0.376

Gnomad4 EAS AF: 0.870

Gnomad4 SAS AF: 0.462

Gnomad4 FIN AF: 0.496

Gnomad4 NFE AF: 0.382

Gnomad4 OTH AF: 0.423

Alfa AF: 0.391 Hom.: 23433

Bravo AF: 0.436

Asia WGS AF: 0.624 AC: 2165 AN: 3478

EpiCase AF: 0.373

EpiControl AF: 0.377

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Obesity due to leptin receptor gene deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 specified Benign:2

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.33
DANN	Benign	0.34

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: rs1805096; hg19: chr1-66102257; COSMIC: COSV62746481; COSMIC: COSV62746481;