chr7-128241296-G-A

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.-39G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 154,068 control chromosomes in the GnomAD database, including 10,689 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 10565 hom., cov: 33)

Exomes 𝑓: 0.34 ( 124 hom. )

Consequence

LEP
NM_000230.3 5_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.12

Publications

194 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=-0.79).

BP6

Variant 7-128241296-G-A is Benign according to our data. Variant chr7-128241296-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 358814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEP	NM_000230.3 link	c.-39G>A		5_prime_UTR_variant	Exon 1 of 3	ENST00000308868.5	NP_000221.1	P41159A4D0Y8
LEP	XM_005250340.6 link	c.-39G>A		5_prime_UTR_variant	Exon 1 of 3		XP_005250397.1	P41159

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEP	ENST00000308868.5 link	c.-39G>A		5_prime_UTR_variant	Exon 1 of 3	1	NM_000230.3	ENSP00000312652.4		P41159
ENSG00000289434	ENST00000785131.1 link	n.169-19756C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.370

AC:

56252

AN:

151972

Hom.:

10557

Cov.:

show subpopulations

Gnomad AFR

AF:

0.408

Gnomad AMI

AF:

0.313

Gnomad AMR

AF:

0.378

Gnomad ASJ

AF:

0.350

Gnomad EAS

AF:

0.199

Gnomad SAS

AF:

0.295

Gnomad FIN

AF:

0.342

Gnomad MID

AF:

0.348

Gnomad NFE

AF:

0.370

Gnomad OTH

AF:

0.366

GnomAD4 exome

AF:

0.335

AC:

663

AN:

1978

Hom.:

124

Cov.:

AF XY:

0.337

AC XY:

361

AN XY:

1072

show subpopulations

African (AFR)

AF:

0.594

AC:

AN:

American (AMR)

AF:

0.417

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.462

AC:

AN:

East Asian (EAS)

AF:

0.141

AC:

AN:

192

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AF:

0.354

AC:

204

AN:

576

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.344

AC:

355

AN:

1032

Other (OTH)

AF:

0.350

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.370

AC:

56309

AN:

152090

Hom.:

10565

Cov.:

AF XY:

0.366

AC XY:

27225

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.409

AC:

16960

AN:

41510

American (AMR)

AF:

0.378

AC:

5776

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.350

AC:

1213

AN:

3468

East Asian (EAS)

AF:

0.198

AC:

1023

AN:

5156

South Asian (SAS)

AF:

0.295

AC:

1423

AN:

4830

European-Finnish (FIN)

AF:

0.342

AC:

3619

AN:

10590

Middle Eastern (MID)

AF:

0.347

AC:

102

AN:

294

European-Non Finnish (NFE)

AF:

0.370

AC:

25141

AN:

67946

Other (OTH)

AF:

0.364

AC:

767

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1826

3651

5477

7302

9128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.375

Hom.:

15000

Bravo

AF:

0.380

Asia WGS

AF:

0.238

AC:

830

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 21, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23751306) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.68

PhyloP100

2.1

PromoterAI

-0.16

Neutral

(source)

Mutation Taster

=300/0

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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chr7-128241296-G-A

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