dbSNP rs10244329: LEP:c.-28-3355A>T (chr7-128248636-A-T) – 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.-28-3355A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.499 in 152,082 control chromosomes in the GnomAD database, including 19,226 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 0.50 ( 19226 hom., cov: 33)

Consequence

LEP
NM_000230.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.692

Publications

22 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=-0.99).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEP	NM_000230.3 link	c.-28-3355A>T		intron_variant	Intron 1 of 2	ENST00000308868.5	NP_000221.1	P41159A4D0Y8
LEP	XM_005250340.6 link	c.-28-3355A>T		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.-28-3355A>T	intron_variant	Intron 1 of 2	1	NM_000230.3	ENSP00000312652.4	P41159
ENSG00000289434	ENST00000785131.1 link	n.168+14726T>A	intron_variant	Intron 1 of 1
ENSG00000302259	ENST00000785222.1 link	n.236-2043A>T	intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.499

AC:

75831

AN:

151964

Hom.:

19212

Cov.:

show subpopulations

Gnomad AFR

AF:

0.538

Gnomad AMI

AF:

0.550

Gnomad AMR

AF:

0.493

Gnomad ASJ

AF:

0.527

Gnomad EAS

AF:

0.265

Gnomad SAS

AF:

0.460

Gnomad FIN

AF:

0.462

Gnomad MID

AF:

0.535

Gnomad NFE

AF:

0.500

Gnomad OTH

AF:

0.526

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

GnomAD4 genome

AF:

0.499

AC:

75893

AN:

152082

Hom.:

19226

Cov.:

AF XY:

0.494

AC XY:

36691

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.538

AC:

22348

AN:

41502

American (AMR)

AF:

0.494

AC:

7536

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.527

AC:

1830

AN:

3470

East Asian (EAS)

AF:

0.264

AC:

1371

AN:

5186

South Asian (SAS)

AF:

0.460

AC:

2220

AN:

4828

European-Finnish (FIN)

AF:

0.462

AC:

4869

AN:

10544

Middle Eastern (MID)

AF:

0.534

AC:

156

AN:

292

European-Non Finnish (NFE)

AF:

0.500

AC:

33959

AN:

67970

Other (OTH)

AF:

0.522

AC:

1102

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1967

3933

5900

7866

9833

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

676

1352

2028

2704

3380

<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:

0.510

Hom.:

2465

Bravo

AF:

0.505

Asia WGS

AF:

0.348

AC:

1212

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.99

CADD

Benign

1.4

(source)

DANN

Benign

0.39

PhyloP100

-0.69

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