rs2060713

chr7-128246976-T-C

Variant summary

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

The NM_000230.3(LEP):c.-28-5015T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.926 in 152,228 control chromosomes in the GnomAD database, including 65,433 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 0.93 (65433 hom., cov: 31)
• Consequence: LEP NM_000230.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.59

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=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEP	NM_000230.3	c.-28-5015T>C		intron_variant		ENST00000308868.5
LEP	XM_005250340.6	c.-28-5015T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEP	ENST00000308868.5	c.-28-5015T>C		intron_variant		1	NM_000230.3	P1

Frequencies

GnomAD3 genomes AF: 0.927 AC: 140936 AN: 152110 Hom.: 65387 Cov.: 31

Gnomad AFR AF: 0.880

Gnomad AMI AF: 0.988

Gnomad AMR AF: 0.954

Gnomad ASJ AF: 0.950

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.987

Gnomad FIN AF: 0.926

Gnomad MID AF: 0.984

Gnomad NFE AF: 0.936

Gnomad OTH AF: 0.946

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

GnomAD4 genome AF: 0.926 AC: 141039 AN: 152228 Hom.: 65433 Cov.: 31 AF XY: 0.929 AC XY: 69116 AN XY: 74426

Gnomad4 AFR AF: 0.880

Gnomad4 AMR AF: 0.954

Gnomad4 ASJ AF: 0.950

Gnomad4 EAS AF: 0.998

Gnomad4 SAS AF: 0.987

Gnomad4 FIN AF: 0.926

Gnomad4 NFE AF: 0.936

Gnomad4 OTH AF: 0.946

Alfa AF: 0.924 Hom.: 8698

Bravo AF: 0.926

Asia WGS AF: 0.989 AC: 3439 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.86
Dann	Benign	0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs2060713; hg19: chr7-127887029;