1-65425307-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BA1

The NM_002303.6(LEPR):c.-92C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00435 in 1,612,392 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0068 ( 41 hom., cov: 32)

Exomes 𝑓: 0.0041 ( 165 hom. )

Consequence

LEPR
NM_002303.6 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -0.785

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:

LEPROT (HGNC:29477): (leptin receptor overlapping transcript) LEPROT is associated with the Golgi complex and endosomes and has a role in cell surface expression of growth hormone receptor (GHR; MIM 600946) and leptin receptor (OBR, or LEPR; MIM 601007), thereby altering receptor-mediated cell signaling (Couturier et al., 2007 [PubMed 18042720]; Touvier et al., 2009 [PubMed 19907080]).[supplied by OMIM, Jul 2010]

LEPROT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 1-65425307-C-T is Benign according to our data. Variant chr1-65425307-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 297984.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2, Likely_benign=1}.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6 link	c.-92C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 20	ENST00000349533.11	NP_002294.2	P48357-1
LEPROT	NM_017526.5 link	c.21C>T	p.Leu7Leu	synonymous_variant	Exon 2 of 4	ENST00000371065.9	NP_059996.1	O15243
LEPR	NM_002303.6 link	c.-92C>T		5_prime_UTR_variant	Exon 2 of 20	ENST00000349533.11	NP_002294.2	P48357-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LEPR	ENST00000349533 link	c.-92C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 20	1	NM_002303.6	ENSP00000330393.7	P48357-1
LEPROT	ENST00000371065.9 link	c.21C>T	p.Leu7Leu	synonymous_variant	Exon 2 of 4	1	NM_017526.5	ENSP00000360104.4	O15243
LEPR	ENST00000349533 link	c.-92C>T		5_prime_UTR_variant	Exon 2 of 20	1	NM_002303.6	ENSP00000330393.7	P48357-1

Frequencies

GnomAD3 genomes

AF:

0.00680

AC:

1035

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000917

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0554

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0562

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00118

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00926

AC:

2289

AN:

247190

Hom.:

AF XY:

0.00902

AC XY:

1207

AN XY:

133888

show subpopulations

Gnomad AFR exome

AF:

0.00161

Gnomad AMR exome

AF:

0.000502

Gnomad ASJ exome

AF:

0.000299

Gnomad EAS exome

AF:

0.0458

Gnomad SAS exome

AF:

0.000923

Gnomad FIN exome

AF:

0.0546

Gnomad NFE exome

AF:

0.00134

Gnomad OTH exome

AF:

0.00841

GnomAD4 exome

AF:

0.00410

AC:

5985

AN:

1460118

Hom.:

165

Cov.:

AF XY:

0.00402

AC XY:

2921

AN XY:

726368

show subpopulations

Gnomad4 AFR exome

AF:

0.000960

Gnomad4 AMR exome

AF:

0.000543

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.0582

Gnomad4 SAS exome

AF:

0.000849

Gnomad4 FIN exome

AF:

0.0513

Gnomad4 NFE exome

AF:

0.000408

Gnomad4 OTH exome

AF:

0.00577

GnomAD4 genome

AF:

0.00680

AC:

1035

AN:

152274

Hom.:

Cov.:

AF XY:

0.00942

AC XY:

701

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.000914

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.0553

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.0562

Gnomad4 NFE

AF:

0.00118

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00103

Hom.:

Bravo

AF:

0.00255

Asia WGS

AF:

0.0220

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 27, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 20, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Monogenic Non-Syndromic Obesity

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Obesity due to leptin receptor gene deficiency

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

6.4

DANN

Benign

0.78

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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