1-65636536-A-T

Position:

chr1-65636536-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002303.6(LEPR):c.3019A>T(p.Ser1007Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000766 in 1,614,120 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00054 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00079 ( 15 hom. )

Consequence

LEPR
NM_002303.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 0.348

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0070999265).

BP6

Variant 1-65636536-A-T is Benign according to our data. Variant chr1-65636536-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 297999.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=1}. Variant chr1-65636536-A-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000538 (82/152320) while in subpopulation SAS AF= 0.00892 (43/4820). AF 95% confidence interval is 0.00681. There are 2 homozygotes in gnomad4. There are 59 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LEPR	NM_002303.6 linkuse as main transcript	c.3019A>T	p.Ser1007Cys	missense_variant	20/20	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.3019A>T	p.Ser1007Cys	missense_variant	20/20	1	NM_002303.6	ENSP00000330393.7		P48357-1

Frequencies

GnomAD3 genomes

AF:

0.000539

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00871

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00160

AC:

401

AN:

250532

Hom.:

AF XY:

0.00207

AC XY:

281

AN XY:

135428

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.000811

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00974

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000372

Gnomad OTH exome

AF:

0.00213

GnomAD4 exome

AF:

0.000789

AC:

1154

AN:

1461800

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

756

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000872

Gnomad4 ASJ exome

AF:

0.00153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00901

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000147

Gnomad4 OTH exome

AF:

0.00149

GnomAD4 genome

AF:

0.000538

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000792

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00892

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000447

Hom.:

Bravo

AF:

0.000264

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00184

AC:

223

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 13, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2020	See Variant Classification Assertion Criteria. -

Monogenic Non-Syndromic Obesity

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Obesity due to leptin receptor gene deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

- -

Monogenic diabetes

Benign:1

Likely benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jun 01, 2017

ACMG Criteria:PP3 (3 predictors), BP4 (7 predictors), BS2 (4 homozygotes in South Asian in ExAC, 35 cases and 40 controls in type2diabetesgenetics.org), BP5 (found in case with GCK pathogenic variant) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Uncertain

0.51

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.72

M_CAP

Benign

0.0099

MetaRNN

Benign

0.0071

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.078

Sift

Benign

0.12

Sift4G

Benign

0.20

Polyphen

0.061

Vest4

0.14

MVP

0.61

MPC

0.11

ClinPred

0.016

GERP RS

3.7

Varity_R

0.12

gMVP

0.40

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