rs12706832

chr7-128247086-A-G

Variant summary

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

The NM_000230.3(LEP):c.-28-4905A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.453 in 152,080 control chromosomes in the GnomAD database, including 17,682 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 0.45 (17682 hom., cov: 32)
• Consequence: LEP NM_000230.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.603

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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEP	NM_000230.3	c.-28-4905A>G		intron_variant		ENST00000308868.5
LEP	XM_005250340.6	c.-28-4905A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEP	ENST00000308868.5	c.-28-4905A>G		intron_variant		1	NM_000230.3	P1

Frequencies

GnomAD3 genomes AF: 0.454 AC: 68941 AN: 151962 Hom.: 17677 Cov.: 32

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.520

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.734

Gnomad SAS AF: 0.562

Gnomad FIN AF: 0.523

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.543

Gnomad OTH AF: 0.483

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

GnomAD4 genome AF: 0.453 AC: 68956 AN: 152080 Hom.: 17682 Cov.: 32 AF XY: 0.458 AC XY: 34064 AN XY: 74330

Gnomad4 AFR AF: 0.204

Gnomad4 AMR AF: 0.520

Gnomad4 ASJ AF: 0.534

Gnomad4 EAS AF: 0.734

Gnomad4 SAS AF: 0.561

Gnomad4 FIN AF: 0.523

Gnomad4 NFE AF: 0.543

Gnomad4 OTH AF: 0.486

Alfa AF: 0.539 Hom.: 36841

Bravo AF: 0.440

Asia WGS AF: 0.641 AC: 2227 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	2.3
Dann	Benign	0.67

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: rs12706832; hg19: chr7-127887139;