Genetic Variant LEP:c.-28-1893A>G (chr7-128250098-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.-28-1893A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.924 in 152,206 control chromosomes in the GnomAD database, including 65,162 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 0.92 ( 65162 hom., cov: 31)

Consequence

LEP
NM_000230.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.03

Publications

12 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=-0.88).

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.-28-1893A>G		intron_variant	Intron 1 of 2	ENST00000308868.5	NP_000221.1
LEP	XM_005250340.6 link	c.-28-1893A>G		intron_variant	Intron 1 of 2		XP_005250397.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
LEP	ENST00000308868.5 link	c.-28-1893A>G	intron_variant	Intron 1 of 2	1	NM_000230.3	ENSP00000312652.4
ENSG00000289434	ENST00000785131.1 link	n.168+13264T>C	intron_variant	Intron 1 of 1
ENSG00000302259	ENST00000785222.1 link	n.236-581A>G	intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.925

AC:

140606

AN:

152088

Hom.:

65114

Cov.:

show subpopulations

Gnomad AFR

AF:

0.873

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:

0.978

Gnomad NFE

AF:

0.936

Gnomad OTH

AF:

0.944

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

GnomAD4 genome

AF:

0.924

AC:

140712

AN:

152206

Hom.:

65162

Cov.:

AF XY:

0.926

AC XY:

68945

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.873

AC:

36217

AN:

41494

American (AMR)

AF:

0.954

AC:

14591

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.950

AC:

3296

AN:

3470

East Asian (EAS)

AF:

0.998

AC:

5168

AN:

5176

South Asian (SAS)

AF:

0.986

AC:

4760

AN:

4826

European-Finnish (FIN)

AF:

0.926

AC:

9814

AN:

10600

Middle Eastern (MID)

AF:

0.976

AC:

287

AN:

294

European-Non Finnish (NFE)

AF:

0.936

AC:

63681

AN:

68024

Other (OTH)

AF:

0.944

AC:

1997

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

527

1054

1582

2109

2636

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

908

1816

2724

3632

4540

<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:

0.934

Hom.:

82603

Bravo

AF:

0.924

Asia WGS

AF:

0.987

AC:

3433

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.45

(source)

DANN

Benign

0.72

PhyloP100

-2.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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