rs2278815

Variant names:

• chr7-128241798-G-A
• rs2278815
• NM_000230.3:c.-29+492G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-128241798-G-A
• chr7-128241798-G-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.-29+492G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 152,100 control chromosomes in the GnomAD database, including 17,856 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 0.44 (17856 hom., cov: 33)
• Consequence: LEP NM_000230.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.166
• Publications: 15 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEP	NM_000230.3	c.-29+492G>A		intron_variant	Intron 1 of 2	ENST00000308868.5	NP_000221.1
LEP	XM_005250340.6	c.-29+492G>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.-29+492G>A		intron_variant	Intron 1 of 2	1	NM_000230.3	ENSP00000312652.4
ENSG00000289434	ENST00000785131.1	n.169-20258C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67496 AN: 151982 Hom.: 17852 Cov.: 33

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.647

Gnomad AMR AF: 0.514

Gnomad ASJ AF: 0.528

Gnomad EAS AF: 0.742

Gnomad SAS AF: 0.606

Gnomad FIN AF: 0.560

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.553

Gnomad OTH AF: 0.473

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

GnomAD4 genome AF: 0.444 AC: 67514 AN: 152100 Hom.: 17856 Cov.: 33 AF XY: 0.452 AC XY: 33571 AN XY: 74338

African (AFR) AF: 0.140 AC: 5804 AN: 41528

American (AMR) AF: 0.513 AC: 7845 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.528 AC: 1830 AN: 3466

East Asian (EAS) AF: 0.743 AC: 3843 AN: 5170

South Asian (SAS) AF: 0.607 AC: 2924 AN: 4818

European-Finnish (FIN) AF: 0.560 AC: 5917 AN: 10560

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.553 AC: 37593 AN: 67958

Other (OTH) AF: 0.476 AC: 1006 AN: 2112

Alfa AF: 0.514 Hom.: 26871

Bravo AF: 0.423

Asia WGS AF: 0.656 AC: 2277 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.7
DANN	Benign	0.80
PhyloP100		-0.17
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: rs2278815; hg19: chr7-127881851;