dbSNP rs3790425: LEPR:c.494+4980A>G (chr1-65577429-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002303.6(LEPR):c.494+4980A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 152,578 control chromosomes in the GnomAD database, including 7,780 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 0.29 ( 7711 hom., cov: 32)

Exomes 𝑓: 0.32 ( 69 hom. )

Consequence

LEPR
NM_002303.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.88

Publications

7 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:

ENSG00000224570 (HGNC:):

ENSG00000224570 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=-0.92).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6 link	c.494+4980A>G		intron_variant	Intron 5 of 19	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11 link	c.494+4980A>G		intron_variant	Intron 5 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes

AF:

0.290

AC:

43882

AN:

151252

Hom.:

7699

Cov.:

show subpopulations

Gnomad AFR

AF:

0.241

Gnomad AMI

AF:

0.184

Gnomad AMR

AF:

0.286

Gnomad ASJ

AF:

0.168

Gnomad EAS

AF:

0.830

Gnomad SAS

AF:

0.196

Gnomad FIN

AF:

0.376

Gnomad MID

AF:

0.118

Gnomad NFE

AF:

0.281

Gnomad OTH

AF:

0.276

GnomAD4 exome

AF:

0.323

AC:

391

AN:

1210

Hom.:

Cov.:

AF XY:

0.339

AC XY:

207

AN XY:

610

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.875

AC:

AN:

South Asian (SAS)

AF:

0.333

AC:

AN:

European-Finnish (FIN)

AF:

0.353

AC:

318

AN:

900

Middle Eastern (MID)

AF:

0.0806

AC:

AN:

124

European-Non Finnish (NFE)

AF:

0.303

AC:

AN:

132

Other (OTH)

AF:

0.429

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.290

AC:

43935

AN:

151368

Hom.:

7711

Cov.:

AF XY:

0.295

AC XY:

21808

AN XY:

74020

show subpopulations

African (AFR)

AF:

0.242

AC:

9853

AN:

40780

American (AMR)

AF:

0.286

AC:

4371

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.168

AC:

583

AN:

3470

East Asian (EAS)

AF:

0.830

AC:

4286

AN:

5166

South Asian (SAS)

AF:

0.197

AC:

948

AN:

4818

European-Finnish (FIN)

AF:

0.376

AC:

3976

AN:

10564

Middle Eastern (MID)

AF:

0.116

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.281

AC:

19128

AN:

67986

Other (OTH)

AF:

0.279

AC:

588

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1495

2990

4485

5980

7475

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

436

872

1308

1744

2180

<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:

0.269

Hom.:

1703

Bravo

AF:

0.285

Asia WGS

AF:

0.435

AC:

1508

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

2.5

(source)

DANN

Benign

0.45

PhyloP100

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over