rs2025804

Variant names:

• chr1-65480438-G-A
• rs2025804
• NM_002303.6:c.-21+55060G>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+55060G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.679 in 151,872 control chromosomes in the GnomAD database, including 36,191 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 0.68 (36191 hom., cov: 30)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0840
• Publications: 26 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.784 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.-21+55060G>A		intron_variant	Intron 2 of 19	ENST00000349533.11	NP_002294.2
LEPR	NM_001003680.3	c.-21+55060G>A		intron_variant	Intron 2 of 19		NP_001003680.1
LEPR	NM_001003679.3	c.-21+55060G>A		intron_variant	Intron 2 of 19		NP_001003679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.-21+55060G>A		intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7
LEPR	ENST00000371059.7	c.-21+55060G>A		intron_variant	Intron 2 of 19	1		ENSP00000360098.3
LEPR	ENST00000371060.7	c.-21+55060G>A		intron_variant	Intron 2 of 19	1		ENSP00000360099.3

Frequencies

GnomAD3 genomes AF: 0.679 AC: 103045 AN: 151754 Hom.: 36153 Cov.: 30

Gnomad AFR AF: 0.791

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.657

Gnomad ASJ AF: 0.792

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.698

Gnomad FIN AF: 0.558

Gnomad MID AF: 0.826

Gnomad NFE AF: 0.668

Gnomad OTH AF: 0.693

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

GnomAD4 genome AF: 0.679 AC: 103139 AN: 151872 Hom.: 36191 Cov.: 30 AF XY: 0.671 AC XY: 49802 AN XY: 74210

African (AFR) AF: 0.791 AC: 32757 AN: 41420

American (AMR) AF: 0.657 AC: 10013 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.792 AC: 2748 AN: 3468

East Asian (EAS) AF: 0.137 AC: 707 AN: 5162

South Asian (SAS) AF: 0.698 AC: 3362 AN: 4820

European-Finnish (FIN) AF: 0.558 AC: 5865 AN: 10508

Middle Eastern (MID) AF: 0.823 AC: 242 AN: 294

European-Non Finnish (NFE) AF: 0.668 AC: 45393 AN: 67934

Other (OTH) AF: 0.692 AC: 1458 AN: 2106

Alfa AF: 0.668 Hom.: 46794

Bravo AF: 0.689

Asia WGS AF: 0.495 AC: 1723 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.0
DANN	Benign	0.53
PhyloP100		0.084
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: rs2025804; hg19: chr1-65946121;