dbSNP rs11763517: LEP:c.-28-1982T>C (chr7-128250009-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.-28-1982T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 152,050 control chromosomes in the GnomAD database, including 12,797 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 0.39 ( 12797 hom., cov: 32)

Consequence

LEP
NM_000230.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0310

Publications

26 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=-0.84).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.484 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEP	NM_000230.3 link	c.-28-1982T>C		intron_variant	Intron 1 of 2	ENST00000308868.5	NP_000221.1	P41159A4D0Y8
LEP	XM_005250340.6 link	c.-28-1982T>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.-28-1982T>C	intron_variant	Intron 1 of 2	1	NM_000230.3	ENSP00000312652.4	P41159
ENSG00000289434	ENST00000785131.1 link	n.168+13353A>G	intron_variant	Intron 1 of 1
ENSG00000302259	ENST00000785222.1 link	n.236-670T>C	intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.389

AC:

59141

AN:

151930

Hom.:

12800

Cov.:

show subpopulations

Gnomad AFR

AF:

0.206

Gnomad AMI

AF:

0.511

Gnomad AMR

AF:

0.440

Gnomad ASJ

AF:

0.478

Gnomad EAS

AF:

0.212

Gnomad SAS

AF:

0.373

Gnomad FIN

AF:

0.439

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.489

Gnomad OTH

AF:

0.425

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

GnomAD4 genome

AF:

0.389

AC:

59160

AN:

152050

Hom.:

12797

Cov.:

AF XY:

0.386

AC XY:

28699

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.206

AC:

8537

AN:

41498

American (AMR)

AF:

0.441

AC:

6725

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.478

AC:

1657

AN:

3470

East Asian (EAS)

AF:

0.211

AC:

1093

AN:

5170

South Asian (SAS)

AF:

0.373

AC:

1795

AN:

4814

European-Finnish (FIN)

AF:

0.439

AC:

4639

AN:

10558

Middle Eastern (MID)

AF:

0.463

AC:

136

AN:

294

European-Non Finnish (NFE)

AF:

0.489

AC:

33223

AN:

67968

Other (OTH)

AF:

0.422

AC:

890

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1746

3492

5238

6984

8730

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

562

1124

1686

2248

2810

<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:

0.468

Hom.:

28871

Bravo

AF:

0.385

Asia WGS

AF:

0.261

AC:

908

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

2.9

(source)

DANN

Benign

0.72

PhyloP100

-0.031

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