rs6588152

Variant names:

• chr1-65573315-T-A
• rs6588152
• NM_002303.6:c.494+866T>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.494+866T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 152,126 control chromosomes in the GnomAD database, including 3,575 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 0.21 (3575 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.960
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.494+866T>A		intron_variant	Intron 5 of 19	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.494+866T>A		intron_variant	Intron 5 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31750 AN: 152008 Hom.: 3575 Cov.: 32

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.290

Gnomad EAS AF: 0.0644

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.210

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

GnomAD4 genome AF: 0.209 AC: 31753 AN: 152126 Hom.: 3575 Cov.: 32 AF XY: 0.209 AC XY: 15550 AN XY: 74360

African (AFR) AF: 0.207 AC: 8591 AN: 41496

American (AMR) AF: 0.147 AC: 2241 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 1007 AN: 3468

East Asian (EAS) AF: 0.0641 AC: 331 AN: 5162

South Asian (SAS) AF: 0.289 AC: 1393 AN: 4824

European-Finnish (FIN) AF: 0.257 AC: 2715 AN: 10574

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14829 AN: 67992

Other (OTH) AF: 0.212 AC: 448 AN: 2112

Alfa AF: 0.218 Hom.: 509

Bravo AF: 0.196

Asia WGS AF: 0.232 AC: 807 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	14
DANN	Benign	0.86
PhyloP100		0.96
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs6588152; hg19: chr1-66038998;