Genetic Variant LEPR:c.-20-55382G>C (chr1-65510164-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_002303.6(LEPR):c.-20-55382G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 152,208 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.020 ( 36 hom., cov: 32)

Consequence

LEPR
NM_002303.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.210

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

obesity due to leptin receptor gene deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

LEPR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0202 (3071/152208) while in subpopulation NFE AF = 0.0308 (2095/67996). AF 95% confidence interval is 0.0297. There are 36 homozygotes in GnomAd4. There are 1486 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
LEPR	NM_002303.6 link	c.-20-55382G>C	intron_variant	Intron 2 of 19	ENST00000349533.11	NP_002294.2
LEPR	NM_001003680.3 link	c.-20-55382G>C	intron_variant	Intron 2 of 19		NP_001003680.1
LEPR	NM_001003679.3 link	c.-20-55382G>C	intron_variant	Intron 2 of 19		NP_001003679.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
LEPR	ENST00000349533.11 link	c.-20-55382G>C	intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7
LEPR	ENST00000371059.7 link	c.-20-55382G>C	intron_variant	Intron 2 of 19	1		ENSP00000360098.3
LEPR	ENST00000371060.7 link	c.-20-55382G>C	intron_variant	Intron 2 of 19	1		ENSP00000360099.3

Frequencies

GnomAD3 genomes

AF:

0.0202

AC:

3071

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00524

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0113

Gnomad ASJ

AF:

0.0427

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00767

Gnomad FIN

AF:

0.0310

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0308

Gnomad OTH

AF:

0.0206

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0202

AC:

3071

AN:

152208

Hom.:

Cov.:

AF XY:

0.0200

AC XY:

1486

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00523

AC:

217

AN:

41516

American (AMR)

AF:

0.0112

AC:

172

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0427

AC:

148

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00788

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0310

AC:

329

AN:

10610

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0308

AC:

2095

AN:

67996

Other (OTH)

AF:

0.0204

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

166

332

497

663

829

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0290

Hom.:

Bravo

AF:

0.0181

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

2.0

(source)

DANN

Benign

0.55

PhyloP100

0.21

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over