rs11761556

Positions:

• chr7-128257016-C-A
• chr7-128257016-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0650

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]

ACMG classification

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	c.*2253C>A		3_prime_UTR_variant	3/3	ENST00000308868.5
LEP	XM_005250340.6	c.*2253C>A		3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEP	ENST00000308868.5	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.: 31

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.: 40 Cov.: 0 AF XY: 0.531 AC XY: 86 AN XY: 162

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.: 31 AF XY: 0.448 AC XY: 33223 AN XY: 74210

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

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

Other links and lift over

dbSNP: rs11761556; hg19: chr7-127897069;