rs2278814

chr7-128241494-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000230.3(LEP):c.-29+188G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 152,316 control chromosomes in the GnomAD database, including 52 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 0.016 (52 hom., cov: 33)
• Consequence: LEP NM_000230.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07

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).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0155 (2367/152316) while in subpopulation EAS AF= 0.0521 (270/5178). AF 95% confidence interval is 0.047. There are 52 homozygotes in gnomad4. There are 1162 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 52 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEP	NM_000230.3	c.-29+188G>A		intron_variant		ENST00000308868.5
LEP	XM_005250340.6	c.-29+188G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEP	ENST00000308868.5	c.-29+188G>A		intron_variant		1	NM_000230.3	P1

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2364 AN: 152198 Hom.: 52 Cov.: 33

Gnomad AFR AF: 0.0386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00792

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.0524

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.0239

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

GnomAD4 genome AF: 0.0155 AC: 2367 AN: 152316 Hom.: 52 Cov.: 33 AF XY: 0.0156 AC XY: 1162 AN XY: 74488

Gnomad4 AFR AF: 0.0387

Gnomad4 AMR AF: 0.00791

Gnomad4 ASJ AF: 0.0349

Gnomad4 EAS AF: 0.0521

Gnomad4 SAS AF: 0.0199

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.0236

Alfa AF: 0.00884 Hom.: 5

Bravo AF: 0.0162

Asia WGS AF: 0.0380 AC: 133 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.38
Dann	Benign	0.62

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: rs2278814; hg19: chr7-127881547;