1-65572385-G-T

Position:

chr1-65572385-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002303.6(LEPR):c.430G>T(p.Val144Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000368 in 1,444,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00038 ( 0 hom. )

Consequence

LEPR
NM_002303.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 0.156

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:

LEPR (HGNC:):

LEPR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.030551732).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LEPR	NM_002303.6 linkuse as main transcript	c.430G>T	p.Val144Leu	missense_variant	5/20	ENST00000349533.11	NP_002294.2	P48357-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11 linkuse as main transcript	c.430G>T	p.Val144Leu	missense_variant	5/20	1	NM_002303.6	ENSP00000330393.7		P48357-1

Frequencies

GnomAD3 genomes

AF:

0.000216

AC:

AN:

138574

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000161

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000455

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000244

Gnomad OTH

AF:

0.00104

GnomAD3 exomes

AF:

0.000158

AC:

AN:

247206

Hom.:

AF XY:

0.000135

AC XY:

AN XY:

133664

show subpopulations

Gnomad AFR exome

AF:

0.000189

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.000260

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000384

AC:

502

AN:

1305672

Hom.:

Cov.:

AF XY:

0.000387

AC XY:

251

AN XY:

647984

show subpopulations

Gnomad4 AFR exome

AF:

0.000105

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.0000994

Gnomad4 NFE exome

AF:

0.000463

Gnomad4 OTH exome

AF:

0.000359

GnomAD4 genome

AF:

0.000216

AC:

AN:

138672

Hom.:

Cov.:

AF XY:

0.000136

AC XY:

AN XY:

66342

show subpopulations

Gnomad4 AFR

AF:

0.000160

Gnomad4 AMR

AF:

0.000455

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000244

Gnomad4 OTH

AF:

0.00103

Alfa

AF:

0.000315

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000584

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000330

EpiControl

AF:

0.000300

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

LEPR-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 18, 2024

The LEPR c.430G>T variant is predicted to result in the amino acid substitution p.Val144Leu. This variant has been reported in a patient with obesity who also carries a variant in PCSK1 (Courbage et al. 2021. PubMed ID: 34097736). This variant was observed in a cohort of individuals with obesity, and in vitro functional studies showed function similar to that of wildtype levels (Supplemental Data Set, Shah et al. 2023. PubMed ID: 36864747). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Monogenic diabetes

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Nov 20, 2015

ACMG Criteria: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.72

CADD

Benign

6.6

DANN

Benign

0.49

DEOGEN2

Benign

0.079

.;.;T;.;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.74

T;.;T;T;T;.

M_CAP

Benign

0.0059

MetaRNN

Benign

0.031

T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.55

N;N;N;N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

0.15

N;N;N;N;.;N

REVEL

Benign

0.052

Sift

Benign

0.99

T;T;T;T;.;T

Sift4G

Benign

1.0

T;T;T;T;T;T

Polyphen

0.0010

B;B;B;B;B;B

Vest4

0.066

MVP

0.22

MPC

0.10

ClinPred

0.0073

GERP RS

-5.3

Varity_R

0.036

gMVP

0.44

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