rs791620

Variant names:

• chr7-128241090-C-A
• rs791620
• NM_000230.3:c.-245C>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000230.3(LEP):​c.-245C>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0728 in 152,074 control chromosomes in the GnomAD database, including 502 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 0.073 (502 hom., cov: 33)
• Consequence: LEP NM_000230.3 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.22

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEP	NM_000230.3	c.-245C>A		upstream_gene_variant		ENST00000308868.5	NP_000221.1
LEP	XM_005250340.6	c.-245C>A		upstream_gene_variant			XP_005250397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEP	ENST00000308868.5	c.-245C>A		upstream_gene_variant		1	NM_000230.3	ENSP00000312652.4

Frequencies

GnomAD3 genomes AF: 0.0727 AC: 11051 AN: 151958 Hom.: 500 Cov.: 33

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0464

Gnomad ASJ AF: 0.0504

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.0741

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.0637

Gnomad OTH AF: 0.0533

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

GnomAD4 genome AF: 0.0728 AC: 11064 AN: 152074 Hom.: 502 Cov.: 33 AF XY: 0.0707 AC XY: 5259 AN XY: 74378

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.0463

Gnomad4 ASJ AF: 0.0504

Gnomad4 EAS AF: 0.00175

Gnomad4 SAS AF: 0.0133

Gnomad4 FIN AF: 0.0741

Gnomad4 NFE AF: 0.0637

Gnomad4 OTH AF: 0.0532

Alfa AF: 0.0719 Hom.: 65

Bravo AF: 0.0728

Asia WGS AF: 0.0110 AC: 38 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.47
DANN	Benign	0.83

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs791620; hg19: chr7-127881143;