rs791620

Variant names:

• chr7-128241090-C-A
• rs791620
• ENST00000785131.1:n.169-19550G>T

Variant summary

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

The ENST00000785131.1(ENSG00000289434):​n.169-19550G>T variant causes a intron 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: ENSG00000289434 ENST00000785131.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.22
• Publications: 11 publications found

Genes affected

ENSG00000289434 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -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
ENSG00000289434	ENST00000785131.1	n.169-19550G>T		intron_variant	Intron 1 of 1
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

African (AFR) AF: 0.118 AC: 4878 AN: 41502

American (AMR) AF: 0.0463 AC: 709 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0504 AC: 175 AN: 3470

East Asian (EAS) AF: 0.00175 AC: 9 AN: 5152

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4824

European-Finnish (FIN) AF: 0.0741 AC: 785 AN: 10600

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.0637 AC: 4324 AN: 67918

Other (OTH) AF: 0.0532 AC: 112 AN: 2104

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
PhyloP100		-3.2
PromoterAI		0.0038	Neutral

Splicing

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

Other links and lift over

dbSNP: rs791620; hg19: chr7-127881143;