rs10493380

Positions:

• chr1-65580434-A-C

Variant summary

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

The ENST00000349533.11(LEPR):​c.494+7985A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 152,268 control chromosomes in the GnomAD database, including 1,915 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 0.15 (1915 hom., cov: 33)
• Consequence: LEPR ENST00000349533.11 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LEPR	NM_002303.6	c.494+7985A>C		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+7985A>C		intron_variant		1	NM_002303.6	ENSP00000330393	P4

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22449 AN: 152150 Hom.: 1916 Cov.: 33

Gnomad AFR AF: 0.0790

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.0402

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.178

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

GnomAD4 genome AF: 0.147 AC: 22449 AN: 152268 Hom.: 1915 Cov.: 33 AF XY: 0.145 AC XY: 10809 AN XY: 74458

Gnomad4 AFR AF: 0.0788

Gnomad4 AMR AF: 0.232

Gnomad4 ASJ AF: 0.184

Gnomad4 EAS AF: 0.0404

Gnomad4 SAS AF: 0.122

Gnomad4 FIN AF: 0.120

Gnomad4 NFE AF: 0.181

Gnomad4 OTH AF: 0.176

Alfa AF: 0.179 Hom.: 3391

Bravo AF: 0.153

Asia WGS AF: 0.0880 AC: 304 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	15
DANN	Benign	0.65

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: rs10493380; hg19: chr1-66046117; COSMIC: COSV60749925; COSMIC: COSV60749925;