dbSNP rs2278814: LEP:c.-29+188G>A (chr7-128241494-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000230.3(LEP):c.-29+188G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 152,316 control chromosomes in the GnomAD database, including 52 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 0.016 ( 52 hom., cov: 33)

Consequence

LEP
NM_000230.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.07

Publications

1 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).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0155 (2367/152316) while in subpopulation EAS AF = 0.0521 (270/5178). AF 95% confidence interval is 0.047. There are 52 homozygotes in GnomAd4. There are 1162 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 52 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEP	NM_000230.3 link	c.-29+188G>A		intron_variant	Intron 1 of 2	ENST00000308868.5	NP_000221.1	P41159A4D0Y8
LEP	XM_005250340.6 link	c.-29+188G>A		intron_variant	Intron 1 of 2		XP_005250397.1	P41159

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEP	ENST00000308868.5 link	c.-29+188G>A		intron_variant	Intron 1 of 2	1	NM_000230.3	ENSP00000312652.4		P41159
ENSG00000289434	ENST00000785131.1 link	n.169-19954C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0155

AC:

2364

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00792

Gnomad ASJ

AF:

0.0349

Gnomad EAS

AF:

0.0524

Gnomad SAS

AF:

0.0201

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00143

Gnomad OTH

AF:

0.0239

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

GnomAD4 genome

AF:

0.0155

AC:

2367

AN:

152316

Hom.:

Cov.:

AF XY:

0.0156

AC XY:

1162

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0387

AC:

1608

AN:

41578

American (AMR)

AF:

0.00791

AC:

121

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0349

AC:

121

AN:

3470

East Asian (EAS)

AF:

0.0521

AC:

270

AN:

5178

South Asian (SAS)

AF:

0.0199

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00143

AC:

AN:

68014

Other (OTH)

AF:

0.0236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

123

246

368

491

614

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0106

Hom.:

Bravo

AF:

0.0162

Asia WGS

AF:

0.0380

AC:

133

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

0.38

(source)

DANN

Benign

0.62

PhyloP100

-1.1

PromoterAI

-0.058

Neutral

(source)

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