rs11760956

Variant names:

• chr7-128251034-G-A
• rs11760956
• NM_000230.3:c.-28-957G>A

Variant summary

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

The NM_000230.3(LEP):​c.-28-957G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 151,946 control chromosomes in the GnomAD database, including 8,149 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 0.31 (8149 hom., cov: 32)
• Consequence: LEP NM_000230.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.120
• Publications: 19 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet

ENSG00000289434 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEP	NM_000230.3	c.-28-957G>A		intron_variant	Intron 1 of 2	ENST00000308868.5	NP_000221.1
LEP	XM_005250340.6	c.-28-957G>A		intron_variant	Intron 1 of 2		XP_005250397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEP	ENST00000308868.5	c.-28-957G>A		intron_variant	Intron 1 of 2	1	NM_000230.3	ENSP00000312652.4
ENSG00000289434	ENST00000785131.1	n.168+12328C>T		intron_variant	Intron 1 of 1
ENSG00000302259	ENST00000785222.1	n.*95G>A		downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47734 AN: 151828 Hom.: 8147 Cov.: 32

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.356

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.209

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.317

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

GnomAD4 genome AF: 0.314 AC: 47762 AN: 151946 Hom.: 8149 Cov.: 32 AF XY: 0.316 AC XY: 23430 AN XY: 74258

African (AFR) AF: 0.183 AC: 7600 AN: 41442

American (AMR) AF: 0.356 AC: 5435 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 1213 AN: 3468

East Asian (EAS) AF: 0.208 AC: 1079 AN: 5180

South Asian (SAS) AF: 0.337 AC: 1624 AN: 4812

European-Finnish (FIN) AF: 0.386 AC: 4069 AN: 10536

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.378 AC: 25699 AN: 67944

Other (OTH) AF: 0.317 AC: 666 AN: 2104

Alfa AF: 0.356 Hom.: 38621

Bravo AF: 0.309

Asia WGS AF: 0.241 AC: 839 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.3
DANN	Benign	0.51
PhyloP100		-0.12
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

Other links and lift over

dbSNP: rs11760956; hg19: chr7-127891087;