1-65587465-C-T

Variant names:

• chr1-65587465-C-T
• rs12042877
• NM_002303.6:c.495-5192C>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.495-5192C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 151,868 control chromosomes in the GnomAD database, including 7,775 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 0.30 (7775 hom., cov: 33)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.388
• 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: 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.811 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.495-5192C>T		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.495-5192C>T		intron_variant	Intron 5 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.301 AC: 45623 AN: 151750 Hom.: 7764 Cov.: 33

Gnomad AFR AF: 0.277

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.291

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.832

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.377

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.277

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

GnomAD4 genome AF: 0.301 AC: 45678 AN: 151868 Hom.: 7775 Cov.: 33 AF XY: 0.304 AC XY: 22592 AN XY: 74226

African (AFR) AF: 0.277 AC: 11490 AN: 41426

American (AMR) AF: 0.291 AC: 4444 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 594 AN: 3472

East Asian (EAS) AF: 0.831 AC: 4303 AN: 5176

South Asian (SAS) AF: 0.197 AC: 948 AN: 4820

European-Finnish (FIN) AF: 0.377 AC: 3971 AN: 10542

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.282 AC: 19131 AN: 67870

Other (OTH) AF: 0.280 AC: 591 AN: 2110

Alfa AF: 0.280 Hom.: 16797

Bravo AF: 0.297

Asia WGS AF: 0.436 AC: 1513 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	3.2
DANN	Benign	0.59
PhyloP100		0.39
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: rs12042877; hg19: chr1-66053148;