rs11763517

Variant names:

• chr7-128250009-T-C
• rs11763517
• NM_000230.3:c.-28-1982T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000230.3(LEP):​c.-28-1982T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 152,050 control chromosomes in the GnomAD database, including 12,797 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 0.39 (12797 hom., cov: 32)
• Consequence: LEP NM_000230.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0310
• Publications: 26 publications found

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ENSG00000289434 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.484 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000230.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEP	NM_000230.3	MANE Select	c.-28-1982T>C		intron	N/A	NP_000221.1	P41159

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEP	ENST00000308868.5	TSL:1 MANE Select	c.-28-1982T>C		intron	N/A	ENSP00000312652.4	P41159
	LEP	ENST00000965599.1		c.-28-1982T>C		intron	N/A	ENSP00000635658.1
	ENSG00000289434	ENST00000785131.1		n.168+13353A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.389 AC: 59141 AN: 151930 Hom.: 12800 Cov.: 32

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.440

Gnomad ASJ AF: 0.478

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.439

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.489

Gnomad OTH AF: 0.425

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

GnomAD4 genome AF: 0.389 AC: 59160 AN: 152050 Hom.: 12797 Cov.: 32 AF XY: 0.386 AC XY: 28699 AN XY: 74306

African (AFR) AF: 0.206 AC: 8537 AN: 41498

American (AMR) AF: 0.441 AC: 6725 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 1657 AN: 3470

East Asian (EAS) AF: 0.211 AC: 1093 AN: 5170

South Asian (SAS) AF: 0.373 AC: 1795 AN: 4814

European-Finnish (FIN) AF: 0.439 AC: 4639 AN: 10558

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.489 AC: 33223 AN: 67968

Other (OTH) AF: 0.422 AC: 890 AN: 2110

Alfa AF: 0.468 Hom.: 28871

Bravo AF: 0.385

Asia WGS AF: 0.261 AC: 908 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.9
DANN	Benign	0.72
PhyloP100		-0.031
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs11763517;

hg19: chr7-127890062;