rs3790425

Positions:

• chr1-65577429-A-G
• chr1-65577429-A-T

Variant summary

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

The NM_002303.6(LEPR):​c.494+4980A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 152,578 control chromosomes in the GnomAD database, including 7,780 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 0.29 (7711 hom., cov: 32)
  • Exomes 𝑓: 0.32 (69 hom.)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.88

Genes affected

LEPR (HGNC:6554): (leptin receptor) The protein encoded by this gene belongs to the gp130 family of cytokine receptors that are known to stimulate gene transcription via activation of cytosolic STAT proteins. This protein is a receptor for leptin (an adipocyte-specific hormone that regulates body weight), and is involved in the regulation of fat metabolism, as well as in a novel hematopoietic pathway that is required for normal lymphopoiesis. Mutations in this gene have been associated with obesity and pituitary dysfunction. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. It is noteworthy that this gene and LEPROT gene (GeneID:54741) share the same promoter and the first 2 exons, however, encode distinct proteins (PMID:9207021).[provided by RefSeq, Nov 2010]

ENSG00000224570 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LEPR	NM_002303.6	c.494+4980A>G		intron_variant		ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.494+4980A>G		intron_variant		1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.290 AC: 43882 AN: 151252 Hom.: 7699 Cov.: 32

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.830

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.118

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.276

GnomAD4 exome AF: 0.323 AC: 391 AN: 1210 Hom.: 69 Cov.: 0 AF XY: 0.339 AC XY: 207 AN XY: 610

Gnomad4 AFR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.875

Gnomad4 SAS exome AF: 0.333

Gnomad4 FIN exome AF: 0.353

Gnomad4 NFE exome AF: 0.303

Gnomad4 OTH exome AF: 0.429

GnomAD4 genome AF: 0.290 AC: 43935 AN: 151368 Hom.: 7711 Cov.: 32 AF XY: 0.295 AC XY: 21808 AN XY: 74020

Gnomad4 AFR AF: 0.242

Gnomad4 AMR AF: 0.286

Gnomad4 ASJ AF: 0.168

Gnomad4 EAS AF: 0.830

Gnomad4 SAS AF: 0.197

Gnomad4 FIN AF: 0.376

Gnomad4 NFE AF: 0.281

Gnomad4 OTH AF: 0.279

Alfa AF: 0.282 Hom.: 1158

Bravo AF: 0.285

Asia WGS AF: 0.435 AC: 1508 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.5
DANN	Benign	0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs3790425; hg19: chr1-66043112;