dbSNP rs12065099: LEPR:c.-21+5247T>C (chr1-65430625-T-C) – 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.-21+5247T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 152,214 control chromosomes in the GnomAD database, including 2,445 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 0.13 ( 2445 hom., cov: 33)

Consequence

LEPR
NM_002303.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00900

Publications

5 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 links:

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:

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=-0.84).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6 link	c.-21+5247T>C		intron_variant	Intron 2 of 19	ENST00000349533.11	NP_002294.2	P48357-1
LEPROT	NM_017526.5 link	c.279+577T>C		intron_variant	Intron 3 of 3	ENST00000371065.9	NP_059996.1	O15243

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11 link	c.-21+5247T>C		intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7		P48357-1
LEPROT	ENST00000371065.9 link	c.279+577T>C		intron_variant	Intron 3 of 3	1	NM_017526.5	ENSP00000360104.4		O15243

Frequencies

GnomAD3 genomes

AF:

0.130

AC:

19802

AN:

152096

Hom.:

2438

Cov.:

show subpopulations

Gnomad AFR

AF:

0.326

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0629

Gnomad ASJ

AF:

0.0645

Gnomad EAS

AF:

0.0269

Gnomad SAS

AF:

0.100

Gnomad FIN

AF:

0.0711

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.0507

Gnomad OTH

AF:

0.118

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

GnomAD4 genome

AF:

0.130

AC:

19838

AN:

152214

Hom.:

2445

Cov.:

AF XY:

0.129

AC XY:

9603

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.326

AC:

13517

AN:

41460

American (AMR)

AF:

0.0626

AC:

958

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0645

AC:

224

AN:

3472

East Asian (EAS)

AF:

0.0268

AC:

139

AN:

5190

South Asian (SAS)

AF:

0.0994

AC:

480

AN:

4828

European-Finnish (FIN)

AF:

0.0711

AC:

755

AN:

10614

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0507

AC:

3449

AN:

68032

Other (OTH)

AF:

0.118

AC:

248

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

790

1580

2370

3160

3950

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

194

388

582

776

970

<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:

0.0754

Hom.:

1208

Bravo

AF:

0.136

Asia WGS

AF:

0.0890

AC:

308

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

4.5

(source)

DANN

Benign

0.58

PhyloP100

0.0090

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over