rs17151922

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000230.3(LEP):c.*400G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0678 in 223,564 control chromosomes in the GnomAD database, including 1,732 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.087 ( 1582 hom., cov: 32)

Exomes 𝑓: 0.026 ( 150 hom. )

Consequence

LEP
NM_000230.3 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.11

Publications

7 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 7-128255163-G-T is Benign according to our data. Variant chr7-128255163-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 358827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEP	NM_000230.3 link	c.*400G>T		3_prime_UTR_variant	Exon 3 of 3	ENST00000308868.5	NP_000221.1	P41159A4D0Y8
LEP	XM_005250340.6 link	c.*400G>T		3_prime_UTR_variant	Exon 3 of 3		XP_005250397.1	P41159

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEP	ENST00000308868.5 link	c.*400G>T		3_prime_UTR_variant	Exon 3 of 3	1	NM_000230.3	ENSP00000312652.4		P41159
ENSG00000289434	ENST00000785131.1 link	n.168+8199C>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0872

AC:

13248

AN:

151966

Hom.:

1574

Cov.:

show subpopulations

Gnomad AFR

AF:

0.273

Gnomad AMI

AF:

0.0385

Gnomad AMR

AF:

0.0399

Gnomad ASJ

AF:

0.0239

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0271

Gnomad FIN

AF:

0.0220

Gnomad MID

AF:

0.0541

Gnomad NFE

AF:

0.0106

Gnomad OTH

AF:

0.0741

GnomAD4 exome

AF:

0.0262

AC:

1875

AN:

71480

Hom.:

150

Cov.:

AF XY:

0.0256

AC XY:

948

AN XY:

37052

show subpopulations

African (AFR)

AF:

0.274

AC:

906

AN:

3306

American (AMR)

AF:

0.0275

AC:

132

AN:

4808

Ashkenazi Jewish (ASJ)

AF:

0.0269

AC:

AN:

1856

East Asian (EAS)

AF:

0.00

AC:

AN:

4882

South Asian (SAS)

AF:

0.0232

AC:

196

AN:

8444

European-Finnish (FIN)

AF:

0.0153

AC:

AN:

2226

Middle Eastern (MID)

AF:

0.0488

AC:

AN:

246

European-Non Finnish (NFE)

AF:

0.0108

AC:

455

AN:

41996

Other (OTH)

AF:

0.0242

AC:

AN:

3716

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

156

234

312

390

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0874

AC:

13285

AN:

152084

Hom.:

1582

Cov.:

AF XY:

0.0848

AC XY:

6302

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.273

AC:

11300

AN:

41436

American (AMR)

AF:

0.0398

AC:

609

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0239

AC:

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5164

South Asian (SAS)

AF:

0.0269

AC:

130

AN:

4826

European-Finnish (FIN)

AF:

0.0220

AC:

233

AN:

10582

Middle Eastern (MID)

AF:

0.0582

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0106

AC:

722

AN:

67996

Other (OTH)

AF:

0.0733

AC:

155

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

510

1019

1529

2038

2548

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

252

378

504

630

<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:

0.0586

Hom.:

1450

Bravo

AF:

0.0970

Asia WGS

AF:

0.0310

AC:

111

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Monogenic Non-Syndromic Obesity

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Obesity due to congenital leptin deficiency

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.1

(source)

DANN

Benign

0.73

PhyloP100

1.1

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over