1-65568013-T-G

Variant names:

• chr1-65568013-T-G
• rs10158279
• NM_002303.6:c.40+2408T>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.40+2408T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 152,012 control chromosomes in the GnomAD database, including 21,507 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 0.52 (21507 hom., cov: 31)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34
• Publications: 8 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=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.40+2408T>G		intron_variant	Intron 3 of 19	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.40+2408T>G		intron_variant	Intron 3 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.524 AC: 79526 AN: 151894 Hom.: 21487 Cov.: 31

Gnomad AFR AF: 0.516

Gnomad AMI AF: 0.324

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.466

Gnomad EAS AF: 0.890

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.637

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.510

Gnomad OTH AF: 0.498

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

GnomAD4 genome AF: 0.524 AC: 79589 AN: 152012 Hom.: 21507 Cov.: 31 AF XY: 0.527 AC XY: 39152 AN XY: 74292

African (AFR) AF: 0.516 AC: 21383 AN: 41466

American (AMR) AF: 0.446 AC: 6807 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.466 AC: 1615 AN: 3466

East Asian (EAS) AF: 0.890 AC: 4606 AN: 5176

South Asian (SAS) AF: 0.489 AC: 2356 AN: 4814

European-Finnish (FIN) AF: 0.637 AC: 6724 AN: 10560

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.510 AC: 34630 AN: 67946

Other (OTH) AF: 0.503 AC: 1064 AN: 2114

Alfa AF: 0.503 Hom.: 47429

Bravo AF: 0.508

Asia WGS AF: 0.667 AC: 2314 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.43
DANN	Benign	0.58
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs10158279; hg19: chr1-66033696;