dbSNP rs2060713: LEP:c.-28-5015T>C (chr7-128246976-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_000230.3(LEP):c.-28-5015T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.926 in 152,228 control chromosomes in the GnomAD database, including 65,433 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 0.93 ( 65433 hom., cov: 31)

Consequence

LEP
NM_000230.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.59

Publications

9 publications found

Variant links:

Genes affected

LEP (HGNC:6553): (leptin) This gene encodes a protein that is secreted by white adipocytes into the circulation and plays a major role in the regulation of energy homeostasis. Circulating leptin binds to the leptin receptor in the brain, which activates downstream signaling pathways that inhibit feeding and promote energy expenditure. This protein also has several endocrine functions, and is involved in the regulation of immune and inflammatory responses, hematopoiesis, angiogenesis, reproduction, bone formation and wound healing. Mutations in this gene and its regulatory regions cause severe obesity and morbid obesity with hypogonadism in human patients. A mutation in this gene has also been linked to type 2 diabetes mellitus development. [provided by RefSeq, Aug 2017]

LEP Gene-Disease associations (from GenCC):

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

LEP links:

ENSG00000289434 (HGNC:):

ENSG00000289434 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=-1.01).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEP	NM_000230.3 link	c.-28-5015T>C		intron_variant	Intron 1 of 2	ENST00000308868.5	NP_000221.1	P41159A4D0Y8
LEP	XM_005250340.6 link	c.-28-5015T>C		intron_variant	Intron 1 of 2		XP_005250397.1	P41159

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
LEP	ENST00000308868.5 link	c.-28-5015T>C	intron_variant	Intron 1 of 2	1	NM_000230.3	ENSP00000312652.4	P41159
ENSG00000289434	ENST00000785131.1 link	n.168+16386A>G	intron_variant	Intron 1 of 1
ENSG00000302259	ENST00000785222.1 link	n.235+2442T>C	intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.927

AC:

140936

AN:

152110

Hom.:

65387

Cov.:

show subpopulations

Gnomad AFR

AF:

0.880

Gnomad AMI

AF:

0.988

Gnomad AMR

AF:

0.954

Gnomad ASJ

AF:

0.950

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.987

Gnomad FIN

AF:

0.926

Gnomad MID

AF:

0.984

Gnomad NFE

AF:

0.936

Gnomad OTH

AF:

0.946

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

GnomAD4 genome

AF:

0.926

AC:

141039

AN:

152228

Hom.:

65433

Cov.:

AF XY:

0.929

AC XY:

69116

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.880

AC:

36515

AN:

41510

American (AMR)

AF:

0.954

AC:

14600

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.950

AC:

3298

AN:

3472

East Asian (EAS)

AF:

0.998

AC:

5170

AN:

5178

South Asian (SAS)

AF:

0.987

AC:

4762

AN:

4826

European-Finnish (FIN)

AF:

0.926

AC:

9821

AN:

10610

Middle Eastern (MID)

AF:

0.983

AC:

289

AN:

294

European-Non Finnish (NFE)

AF:

0.936

AC:

63687

AN:

68020

Other (OTH)

AF:

0.946

AC:

1996

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

515

1030

1544

2059

2574

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

910

1820

2730

3640

4550

<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:

0.922

Hom.:

8997

Bravo

AF:

0.926

Asia WGS

AF:

0.989

AC:

3439

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.86

(source)

DANN

Benign

0.54

PhyloP100

-3.6

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