rs11585329

Variant names:

• chr1-65608131-G-T
• rs11585329
• NM_002303.6:c.1604-622G>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.1604-622G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 148,890 control chromosomes in the GnomAD database, including 1,201 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 0.11 (1201 hom., cov: 31)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0450
• Publications: 20 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=-0.76).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.1604-622G>T		intron_variant	Intron 11 of 19	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.1604-622G>T		intron_variant	Intron 11 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16331 AN: 148830 Hom.: 1199 Cov.: 31

Gnomad AFR AF: 0.0293

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.00691

Gnomad SAS AF: 0.0954

Gnomad FIN AF: 0.0740

Gnomad MID AF: 0.124

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.124

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

GnomAD4 genome AF: 0.110 AC: 16320 AN: 148890 Hom.: 1201 Cov.: 31 AF XY: 0.106 AC XY: 7648 AN XY: 72396

African (AFR) AF: 0.0292 AC: 1182 AN: 40454

American (AMR) AF: 0.137 AC: 2018 AN: 14774

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 503 AN: 3458

East Asian (EAS) AF: 0.00652 AC: 32 AN: 4910

South Asian (SAS) AF: 0.0953 AC: 451 AN: 4730

European-Finnish (FIN) AF: 0.0740 AC: 713 AN: 9630

Middle Eastern (MID) AF: 0.110 AC: 32 AN: 290

European-Non Finnish (NFE) AF: 0.161 AC: 10910 AN: 67674

Other (OTH) AF: 0.123 AC: 253 AN: 2064

Alfa AF: 0.140 Hom.: 1265

Bravo AF: 0.108

Asia WGS AF: 0.0570 AC: 196 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.4
DANN	Benign	0.82
PhyloP100		-0.045
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: rs11585329; hg19: chr1-66073814;