chr1-65636574-G-A

Position:

chr1-65636574-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.823

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 -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	Protein	UniProt
LEPR	NM_002303.6 linkuse as main transcript	c.3057G>A	p.Pro1019=	synonymous_variant	20/20	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.3057G>A	p.Pro1019=	synonymous_variant	20/20	1	NM_002303.6	ENSP00000330393	P4	P48357-1

Frequencies

GnomAD3 genomes

AF:

0.437

AC:

66340

AN:

151842

Hom.:

15210

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.404

AC XY:

293419

AN XY:

727172

show subpopulations

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.:

AF XY:

0.446

AC XY:

33101

AN XY:

74280

show subpopulations

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -

not specified

Benign:2

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

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

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