Genetic Variant NM_002303.6:c.494+4887C>A (chr1-65577336-C-A) – 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+4887C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 153,120 control chromosomes in the GnomAD database, including 4,254 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 0.22 ( 4180 hom., cov: 32)

Exomes 𝑓: 0.27 ( 74 hom. )

Consequence

LEPR
NM_002303.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.19

Publications

15 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:

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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=-0.76).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6 link	c.494+4887C>A		intron_variant	Intron 5 of 19	ENST00000349533.11	NP_002294.2	P48357-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11 link	c.494+4887C>A		intron_variant	Intron 5 of 19	1	NM_002303.6	ENSP00000330393.7		P48357-1

Frequencies

GnomAD3 genomes

AF:

0.216

AC:

32677

AN:

151284

Hom.:

4178

Cov.:

show subpopulations

Gnomad AFR

AF:

0.238

Gnomad AMI

AF:

0.133

Gnomad AMR

AF:

0.149

Gnomad ASJ

AF:

0.288

Gnomad EAS

AF:

0.0638

Gnomad SAS

AF:

0.284

Gnomad FIN

AF:

0.259

Gnomad MID

AF:

0.217

Gnomad NFE

AF:

0.216

Gnomad OTH

AF:

0.214

GnomAD4 exome

AF:

0.265

AC:

456

AN:

1718

Hom.:

Cov.:

AF XY:

0.255

AC XY:

225

AN XY:

884

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AF:

0.250

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.231

AC:

AN:

European-Finnish (FIN)

AF:

0.274

AC:

353

AN:

1288

Middle Eastern (MID)

AF:

0.167

AC:

AN:

European-Non Finnish (NFE)

AF:

0.241

AC:

AN:

332

Other (OTH)

AF:

0.238

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.524

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:

0.216

AC:

32688

AN:

151402

Hom.:

4180

Cov.:

AF XY:

0.216

AC XY:

15986

AN XY:

74004

show subpopulations

African (AFR)

AF:

0.237

AC:

9672

AN:

40786

American (AMR)

AF:

0.149

AC:

2270

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.288

AC:

997

AN:

3466

East Asian (EAS)

AF:

0.0636

AC:

329

AN:

5176

South Asian (SAS)

AF:

0.283

AC:

1361

AN:

4814

European-Finnish (FIN)

AF:

0.259

AC:

2735

AN:

10576

Middle Eastern (MID)

AF:

0.229

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.216

AC:

14681

AN:

68002

Other (OTH)

AF:

0.216

AC:

455

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1269

2538

3808

5077

6346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

356

712

1068

1424

1780

<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:

0.214

Hom.:

6472

Bravo

AF:

0.205

Asia WGS

AF:

0.232

AC:

807

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

1.2

(source)

DANN

Benign

0.84

PhyloP100

1.2

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