rs10889563

Variant names:

• chr1-65583484-A-G
• rs10889563
• NM_002303.6:c.495-9173A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-65583484-A-G
• chr1-65583484-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000349533.11(LEPR):​c.495-9173A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.514 in 151,822 control chromosomes in the GnomAD database, including 20,731 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 0.51 (20731 hom., cov: 31)
• Consequence: LEPR ENST00000349533.11 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.564
• Publications: 6 publications found

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]

LEPR Gene-Disease associations (from GenCC):

• obesity due to leptin receptor gene deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -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 = 0.872 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000349533.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	NM_002303.6	MANE Select	c.495-9173A>G		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.495-9173A>G		intron	N/A	NP_001003680.1
	LEPR	NM_001198687.2		c.495-9173A>G		intron	N/A	NP_001185616.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.495-9173A>G		intron	N/A	ENSP00000330393.7
	LEPR	ENST00000371059.7	TSL:1	c.495-9173A>G		intron	N/A	ENSP00000360098.3
	LEPR	ENST00000344610.12	TSL:1	c.495-9173A>G		intron	N/A	ENSP00000340884.8

Frequencies

GnomAD3 genomes AF: 0.514 AC: 77909 AN: 151704 Hom.: 20709 Cov.: 31

Gnomad AFR AF: 0.504

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.459

Gnomad EAS AF: 0.894

Gnomad SAS AF: 0.480

Gnomad FIN AF: 0.637

Gnomad MID AF: 0.356

Gnomad NFE AF: 0.498

Gnomad OTH AF: 0.487

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

GnomAD4 genome AF: 0.514 AC: 77983 AN: 151822 Hom.: 20731 Cov.: 31 AF XY: 0.518 AC XY: 38430 AN XY: 74200

African (AFR) AF: 0.504 AC: 20873 AN: 41410

American (AMR) AF: 0.438 AC: 6679 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 1591 AN: 3468

East Asian (EAS) AF: 0.894 AC: 4606 AN: 5152

South Asian (SAS) AF: 0.479 AC: 2311 AN: 4820

European-Finnish (FIN) AF: 0.637 AC: 6702 AN: 10528

Middle Eastern (MID) AF: 0.369 AC: 107 AN: 290

European-Non Finnish (NFE) AF: 0.498 AC: 33791 AN: 67898

Other (OTH) AF: 0.493 AC: 1035 AN: 2100

Alfa AF: 0.499 Hom.: 2717

Bravo AF: 0.499

Asia WGS AF: 0.667 AC: 2317 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.3
DANN	Benign	0.69
PhyloP100		-0.56
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10889563; hg19: chr1-66049167;