dbSNP rs17151913: LEP:c.145-439T>A (chr7-128253965-T-A) – 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.145-439T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0334 in 150,760 control chromosomes in the GnomAD database, including 241 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 0.033 ( 241 hom., cov: 31)

Consequence

LEP
NM_000230.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.137

Publications

2 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=-0.81).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEP	NM_000230.3 link	c.145-439T>A		intron_variant	Intron 2 of 2	ENST00000308868.5	NP_000221.1	P41159A4D0Y8
LEP	XM_005250340.6 link	c.145-442T>A		intron_variant	Intron 2 of 2		XP_005250397.1	P41159

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEP	ENST00000308868.5 link	c.145-439T>A		intron_variant	Intron 2 of 2	1	NM_000230.3	ENSP00000312652.4		P41159
ENSG00000289434	ENST00000785131.1 link	n.168+9397A>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0334

AC:

5031

AN:

150646

Hom.:

240

Cov.:

show subpopulations

Gnomad AFR

AF:

0.110

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0215

Gnomad ASJ

AF:

0.0165

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000419

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00150

Gnomad OTH

AF:

0.0331

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

GnomAD4 genome

AF:

0.0334

AC:

5037

AN:

150760

Hom.:

241

Cov.:

AF XY:

0.0328

AC XY:

2407

AN XY:

73476

show subpopulations

African (AFR)

AF:

0.109

AC:

4479

AN:

40912

American (AMR)

AF:

0.0214

AC:

323

AN:

15122

Ashkenazi Jewish (ASJ)

AF:

0.0165

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5120

South Asian (SAS)

AF:

0.000420

AC:

AN:

4764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10242

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00150

AC:

102

AN:

67832

Other (OTH)

AF:

0.0328

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

210

420

629

839

1049

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0213

Hom.:

Bravo

AF:

0.0395

Asia WGS

AF:

0.00895

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.9

(source)

DANN

Benign

0.65

PhyloP100

-0.14

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