dbSNP rs12706832: LEP:c.-28-4905A>G (chr7-128247086-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_000230.3(LEP):c.-28-4905A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.453 in 152,080 control chromosomes in the GnomAD database, including 17,682 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 0.45 ( 17682 hom., cov: 32)

Consequence

LEP
NM_000230.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.603

Publications

28 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=-0.89).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEP	NM_000230.3 link	c.-28-4905A>G		intron_variant	Intron 1 of 2	ENST00000308868.5	NP_000221.1	P41159A4D0Y8
LEP	XM_005250340.6 link	c.-28-4905A>G		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.-28-4905A>G	intron_variant	Intron 1 of 2	1	NM_000230.3	ENSP00000312652.4	P41159
ENSG00000289434	ENST00000785131.1 link	n.168+16276T>C	intron_variant	Intron 1 of 1
ENSG00000302259	ENST00000785222.1 link	n.235+2552A>G	intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.454

AC:

68941

AN:

151962

Hom.:

17677

Cov.:

show subpopulations

Gnomad AFR

AF:

0.204

Gnomad AMI

AF:

0.646

Gnomad AMR

AF:

0.520

Gnomad ASJ

AF:

0.534

Gnomad EAS

AF:

0.734

Gnomad SAS

AF:

0.562

Gnomad FIN

AF:

0.523

Gnomad MID

AF:

0.557

Gnomad NFE

AF:

0.543

Gnomad OTH

AF:

0.483

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

GnomAD4 genome

AF:

0.453

AC:

68956

AN:

152080

Hom.:

17682

Cov.:

AF XY:

0.458

AC XY:

34064

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.204

AC:

8472

AN:

41510

American (AMR)

AF:

0.520

AC:

7951

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.534

AC:

1853

AN:

3468

East Asian (EAS)

AF:

0.734

AC:

3794

AN:

5166

South Asian (SAS)

AF:

0.561

AC:

2704

AN:

4816

European-Finnish (FIN)

AF:

0.523

AC:

5510

AN:

10544

Middle Eastern (MID)

AF:

0.548

AC:

161

AN:

294

European-Non Finnish (NFE)

AF:

0.543

AC:

36895

AN:

67966

Other (OTH)

AF:

0.486

AC:

1027

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1757

3514

5271

7028

8785

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

620

1240

1860

2480

3100

<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:

0.521

Hom.:

81932

Bravo

AF:

0.440

Asia WGS

AF:

0.641

AC:

2227

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

2.3

(source)

DANN

Benign

0.67

PhyloP100

-0.60

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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