rs7513047

Variant names:

• chr1-65484657-G-A
• rs7513047
• NM_002303.6:c.-21+59279G>A

Variant summary

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

The NM_002303.6(LEPR):​c.-21+59279G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 152,094 control chromosomes in the GnomAD database, including 10,327 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 0.33 (10327 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.408
• Publications: 14 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=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.463 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.-21+59279G>A		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.-21+59279G>A		intron	N/A	NP_001003680.1
	LEPR	NM_001003679.3		c.-21+59279G>A		intron	N/A	NP_001003679.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.-21+59279G>A		intron	N/A	ENSP00000330393.7
	LEPR	ENST00000371059.7	TSL:1	c.-21+59279G>A		intron	N/A	ENSP00000360098.3
	LEPR	ENST00000371060.7	TSL:1	c.-21+59279G>A		intron	N/A	ENSP00000360099.3

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49590 AN: 151976 Hom.: 10332 Cov.: 32

Gnomad AFR AF: 0.0874

Gnomad AMI AF: 0.383

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.0291

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.468

Gnomad OTH AF: 0.361

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

GnomAD4 genome AF: 0.326 AC: 49585 AN: 152094 Hom.: 10327 Cov.: 32 AF XY: 0.321 AC XY: 23831 AN XY: 74346

African (AFR) AF: 0.0873 AC: 3626 AN: 41542

American (AMR) AF: 0.372 AC: 5677 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 1550 AN: 3468

East Asian (EAS) AF: 0.0294 AC: 152 AN: 5178

South Asian (SAS) AF: 0.269 AC: 1295 AN: 4820

European-Finnish (FIN) AF: 0.407 AC: 4298 AN: 10558

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.468 AC: 31767 AN: 67946

Other (OTH) AF: 0.357 AC: 754 AN: 2112

Alfa AF: 0.439 Hom.: 18558

Bravo AF: 0.315

Asia WGS AF: 0.149 AC: 518 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.2
DANN	Benign	0.44
PhyloP100		-0.41
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: rs7513047; hg19: chr1-65950340;