Genetic Variant LEP:c.-28-4976T>G (chr7-128247015-T-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.-28-4976T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 151,968 control chromosomes in the GnomAD database, including 16,907 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 0.43 ( 16907 hom., cov: 32)

Consequence

LEP
NM_000230.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.155

Publications

3 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 = 0.714 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEP	NM_000230.3 link	c.-28-4976T>G		intron_variant	Intron 1 of 2	ENST00000308868.5	NP_000221.1	P41159A4D0Y8
LEP	XM_005250340.6 link	c.-28-4976T>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.-28-4976T>G	intron_variant	Intron 1 of 2	1	NM_000230.3	ENSP00000312652.4	P41159
ENSG00000289434	ENST00000785131.1 link	n.168+16347A>C	intron_variant	Intron 1 of 1
ENSG00000302259	ENST00000785222.1 link	n.235+2481T>G	intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.427

AC:

64816

AN:

151850

Hom.:

16906

Cov.:

show subpopulations

Gnomad AFR

AF:

0.112

Gnomad AMI

AF:

0.647

Gnomad AMR

AF:

0.509

Gnomad ASJ

AF:

0.534

Gnomad EAS

AF:

0.733

Gnomad SAS

AF:

0.560

Gnomad FIN

AF:

0.522

Gnomad MID

AF:

0.551

Gnomad NFE

AF:

0.543

Gnomad OTH

AF:

0.460

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

GnomAD4 genome

AF:

0.426

AC:

64811

AN:

151968

Hom.:

16907

Cov.:

AF XY:

0.432

AC XY:

32080

AN XY:

74244

show subpopulations

African (AFR)

AF:

0.112

AC:

4625

AN:

41466

American (AMR)

AF:

0.508

AC:

7766

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.534

AC:

1852

AN:

3468

East Asian (EAS)

AF:

0.733

AC:

3783

AN:

5158

South Asian (SAS)

AF:

0.560

AC:

2706

AN:

4832

European-Finnish (FIN)

AF:

0.522

AC:

5490

AN:

10510

Middle Eastern (MID)

AF:

0.541

AC:

159

AN:

294

European-Non Finnish (NFE)

AF:

0.543

AC:

36863

AN:

67942

Other (OTH)

AF:

0.463

AC:

977

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1589

3178

4766

6355

7944

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

586

1172

1758

2344

2930

<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:

0.294

Hom.:

1005

Bravo

AF:

0.409

Asia WGS

AF:

0.633

AC:

2199

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

5.0

(source)

DANN

Benign

0.78

PhyloP100

0.15

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