rs11811946

Variant names:

• chr1-65486745-A-G
• rs11811946
• NM_002303.6:c.-21+61367A>G

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+61367A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.569 in 152,002 control chromosomes in the GnomAD database, including 25,400 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 0.57 (25400 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.806
• Publications: 4 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

ENSG00000237852 (HGNC:):

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 (NFE) allele frequency at 95% confidence interval = 0.597 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.-21+61367A>G		intron_variant	Intron 2 of 19	ENST00000349533.11	NP_002294.2
LEPR	NM_001003680.3	c.-21+61367A>G		intron_variant	Intron 2 of 19		NP_001003680.1
LEPR	NM_001003679.3	c.-21+61367A>G		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+61367A>G		intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7
LEPR	ENST00000371059.7	c.-21+61367A>G		intron_variant	Intron 2 of 19	1		ENSP00000360098.3
LEPR	ENST00000371060.7	c.-21+61367A>G		intron_variant	Intron 2 of 19	1		ENSP00000360099.3
ENSG00000237852	ENST00000429871.1	n.101+239A>G		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.569 AC: 86452 AN: 151884 Hom.: 25383 Cov.: 32

Gnomad AFR AF: 0.584

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.597

Gnomad ASJ AF: 0.665

Gnomad EAS AF: 0.0793

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.602

Gnomad OTH AF: 0.587

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

GnomAD4 genome AF: 0.569 AC: 86512 AN: 152002 Hom.: 25400 Cov.: 32 AF XY: 0.561 AC XY: 41677 AN XY: 74312

African (AFR) AF: 0.584 AC: 24217 AN: 41448

American (AMR) AF: 0.596 AC: 9095 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.665 AC: 2303 AN: 3464

East Asian (EAS) AF: 0.0796 AC: 412 AN: 5174

South Asian (SAS) AF: 0.537 AC: 2583 AN: 4814

European-Finnish (FIN) AF: 0.472 AC: 4995 AN: 10582

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.602 AC: 40924 AN: 67956

Other (OTH) AF: 0.584 AC: 1233 AN: 2110

Alfa AF: 0.587 Hom.: 4195

Bravo AF: 0.578

Asia WGS AF: 0.337 AC: 1176 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.62
DANN	Benign	0.41
PhyloP100		-0.81
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: rs11811946; hg19: chr1-65952428;