chr1-65425348-T-G

Position:

chr1-65425348-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017526.5(LEPROT):c.62T>G(p.Leu21Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000485 in 1,607,058 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00050 ( 1 hom. )

Consequence

LEPROT
NM_017526.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.66

Variant links:

Genes affected

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:

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPROT	NM_017526.5 linkuse as main transcript	c.62T>G	p.Leu21Arg	missense_variant	2/4	ENST00000371065.9
LEPR	NM_002303.6 linkuse as main transcript	c.-51T>G		5_prime_UTR_variant	2/20	ENST00000349533.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPROT	ENST00000371065.9 linkuse as main transcript	c.62T>G	p.Leu21Arg	missense_variant	2/4	1	NM_017526.5	P1
LEPR	ENST00000349533.11 linkuse as main transcript	c.-51T>G		5_prime_UTR_variant	2/20	1	NM_002303.6	P4	P48357-1

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000341

AC:

AN:

240258

Hom.:

AF XY:

0.000338

AC XY:

AN XY:

130136

show subpopulations

Gnomad AFR exome

AF:

0.000187

Gnomad AMR exome

AF:

0.000667

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000485

Gnomad OTH exome

AF:

0.000840

GnomAD4 exome

AF:

0.000498

AC:

725

AN:

1454716

Hom.:

Cov.:

AF XY:

0.000468

AC XY:

339

AN XY:

723620

show subpopulations

Gnomad4 AFR exome

AF:

0.000183

Gnomad4 AMR exome

AF:

0.000689

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000594

Gnomad4 OTH exome

AF:

0.000449

GnomAD4 genome

AF:

0.000354

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000349

Hom.:

Bravo

AF:

0.000446

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000280

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000534

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Obesity due to leptin receptor gene deficiency

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

.;D;.;.;T

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Uncertain

0.087

MetaRNN

Uncertain

0.67

D;D;D;D;D

MetaSVM

Uncertain

-0.042

MutationAssessor

Uncertain

2.9

.;M;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-5.1

.;D;.;.;.

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

.;D;.;.;.

Sift4G

Pathogenic

0.0010

.;D;.;.;D

Polyphen

1.0

.;D;.;.;.

Vest4

0.97, 0.96

MVP

0.57

MPC

1.0

ClinPred

0.33

GERP RS

5.7

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.1

Varity_R

0.90

gMVP

0.96

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