Variant 7-128257016-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000230.3(LEP):c.*2253C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 152,118 control chromosomes in the GnomAD database, including 17,319 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.44 ( 17279 hom., cov: 31)

Exomes 𝑓: 0.54 ( 40 hom. )

Consequence

LEP
NM_000230.3 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0650

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BP6

Variant 7-128257016-C-A is Benign according to our data. Variant chr7-128257016-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 358845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.714 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEP	NM_000230.3 linkuse as main transcript	c.*2253C>A		3_prime_UTR_variant	3/3	ENST00000308868.5
LEP	XM_005250340.6 linkuse as main transcript	c.*2253C>A		3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEP	ENST00000308868.5 linkuse as main transcript	c.*2253C>A		3_prime_UTR_variant	3/3	1	NM_000230.3	P1

Frequencies

GnomAD3 genomes

AF:

0.444

AC:

67401

AN:

151726

Hom.:

17271

Cov.:

show subpopulations

Gnomad AFR

AF:

0.175

Gnomad AMI

AF:

0.647

Gnomad AMR

AF:

0.517

Gnomad ASJ

AF:

0.557

Gnomad EAS

AF:

0.732

Gnomad SAS

AF:

0.578

Gnomad FIN

AF:

0.495

Gnomad MID

AF:

0.532

Gnomad NFE

AF:

0.542

Gnomad OTH

AF:

0.483

GnomAD4 exome

AF:

0.540

AC:

148

AN:

274

Hom.:

Cov.:

AF XY:

0.531

AC XY:

AN XY:

162

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.750

Gnomad4 ASJ exome

AF:

0.750

Gnomad4 EAS exome

AF:

0.750

Gnomad4 SAS exome

AF:

0.500

Gnomad4 FIN exome

AF:

0.509

Gnomad4 NFE exome

AF:

0.578

Gnomad4 OTH exome

AF:

0.462

GnomAD4 genome

AF:

0.444

AC:

67426

AN:

151844

Hom.:

17279

Cov.:

AF XY:

0.448

AC XY:

33223

AN XY:

74210

show subpopulations

Gnomad4 AFR

AF:

0.175

Gnomad4 AMR

AF:

0.517

Gnomad4 ASJ

AF:

0.557

Gnomad4 EAS

AF:

0.733

Gnomad4 SAS

AF:

0.578

Gnomad4 FIN

AF:

0.495

Gnomad4 NFE

AF:

0.542

Gnomad4 OTH

AF:

0.489

Alfa

AF:

0.467

Hom.:

4401

Bravo

AF:

0.429

Asia WGS

AF:

0.648

AC:

2251

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Monogenic Non-Syndromic Obesity

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Obesity due to congenital leptin deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.85

DANN

Benign

0.50

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over