rs11808888

Variant names:

• chr1-65487098-G-A
• rs11808888
• NM_002303.6:c.-21+61720G>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+61720G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 152,064 control chromosomes in the GnomAD database, including 6,249 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 0.24 (6249 hom., cov: 33)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.568
• Publications: 5 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ENSG00000237852 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.483 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	NM_002303.6	MANE Select	c.-21+61720G>A		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.-21+61720G>A		intron	N/A	NP_001003680.1	P48357-3
	LEPR	NM_001003679.3		c.-21+61720G>A		intron	N/A	NP_001003679.1	P48357-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.-21+61720G>A		intron	N/A	ENSP00000330393.7	P48357-1
	LEPR	ENST00000371059.7	TSL:1	c.-21+61720G>A		intron	N/A	ENSP00000360098.3	P48357-3
	LEPR	ENST00000371060.7	TSL:1	c.-21+61720G>A		intron	N/A	ENSP00000360099.3	P48357-2

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36475 AN: 151944 Hom.: 6231 Cov.: 33

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.0500

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.0649

Gnomad MID AF: 0.312

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.223

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

GnomAD4 genome AF: 0.240 AC: 36533 AN: 152064 Hom.: 6249 Cov.: 33 AF XY: 0.237 AC XY: 17646 AN XY: 74328

African (AFR) AF: 0.489 AC: 20263 AN: 41452

American (AMR) AF: 0.223 AC: 3399 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 757 AN: 3470

East Asian (EAS) AF: 0.0502 AC: 260 AN: 5184

South Asian (SAS) AF: 0.266 AC: 1281 AN: 4820

European-Finnish (FIN) AF: 0.0649 AC: 686 AN: 10572

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9130 AN: 67988

Other (OTH) AF: 0.224 AC: 473 AN: 2112

Alfa AF: 0.177 Hom.: 3883

Bravo AF: 0.260

Asia WGS AF: 0.185 AC: 650 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.21
DANN	Benign	0.39
PhyloP100		-0.57
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: rs11808888; hg19: chr1-65952781;