rs12564626

Variant names:

• chr1-65590859-G-A
• rs12564626
• NM_002303.6:c.495-1798G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-65590859-G-A
• chr1-65590859-G-T

Variant summary

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

The NM_002303.6(LEPR):​c.495-1798G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 149,986 control chromosomes in the GnomAD database, including 17,210 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 0.47 (17210 hom., cov: 30)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.48
• 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=-1.04).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.854 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002303.6. 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.495-1798G>A		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.495-1798G>A		intron	N/A	NP_001003680.1
	LEPR	NM_001198687.2		c.495-1798G>A		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.495-1798G>A		intron	N/A	ENSP00000330393.7
	LEPR	ENST00000371059.7	TSL:1	c.495-1798G>A		intron	N/A	ENSP00000360098.3
	LEPR	ENST00000344610.12	TSL:1	c.495-1798G>A		intron	N/A	ENSP00000340884.8

Frequencies

GnomAD3 genomes AF: 0.469 AC: 70317 AN: 149910 Hom.: 17201 Cov.: 30

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.274

Gnomad AMR AF: 0.430

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.876

Gnomad SAS AF: 0.492

Gnomad FIN AF: 0.614

Gnomad MID AF: 0.321

Gnomad NFE AF: 0.454

Gnomad OTH AF: 0.450

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

GnomAD4 genome AF: 0.469 AC: 70341 AN: 149986 Hom.: 17210 Cov.: 30 AF XY: 0.477 AC XY: 34937 AN XY: 73206

African (AFR) AF: 0.430 AC: 17588 AN: 40928

American (AMR) AF: 0.431 AC: 6479 AN: 15042

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1406 AN: 3458

East Asian (EAS) AF: 0.876 AC: 4511 AN: 5152

South Asian (SAS) AF: 0.492 AC: 2347 AN: 4772

European-Finnish (FIN) AF: 0.614 AC: 6102 AN: 9944

Middle Eastern (MID) AF: 0.331 AC: 94 AN: 284

European-Non Finnish (NFE) AF: 0.454 AC: 30621 AN: 67428

Other (OTH) AF: 0.456 AC: 945 AN: 2072

Alfa AF: 0.456 Hom.: 2100

Bravo AF: 0.451

Asia WGS AF: 0.665 AC: 2302 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.75
DANN	Benign	0.22
PhyloP100		-1.5
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: rs12564626; hg19: chr1-66056542;