1-65526942-C-T

Variant names:

• chr1-65526942-C-T
• rs1751492
• NM_002303.6:c.-20-38604C>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.-20-38604C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.689 in 152,038 control chromosomes in the GnomAD database, including 37,074 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 0.69 (37074 hom., cov: 33)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.195
• Publications: 35 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.777 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.-20-38604C>T		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.-20-38604C>T		intron	N/A	NP_001003680.1	P48357-3
	LEPR	NM_001198687.2		c.-21+1124C>T		intron	N/A	NP_001185616.1	P48357-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.-20-38604C>T		intron	N/A	ENSP00000330393.7	P48357-1
	LEPR	ENST00000371059.7	TSL:1	c.-20-38604C>T		intron	N/A	ENSP00000360098.3	P48357-3
	LEPR	ENST00000344610.12	TSL:1	c.-21+1124C>T		intron	N/A	ENSP00000340884.8	P48357-4

Frequencies

GnomAD3 genomes AF: 0.690 AC: 104756 AN: 151920 Hom.: 37060 Cov.: 33

Gnomad AFR AF: 0.725

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.703

Gnomad ASJ AF: 0.813

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.798

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.867

Gnomad NFE AF: 0.703

Gnomad OTH AF: 0.720

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

GnomAD4 genome AF: 0.689 AC: 104817 AN: 152038 Hom.: 37074 Cov.: 33 AF XY: 0.685 AC XY: 50883 AN XY: 74322

African (AFR) AF: 0.725 AC: 30040 AN: 41462

American (AMR) AF: 0.702 AC: 10719 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.813 AC: 2824 AN: 3472

East Asian (EAS) AF: 0.165 AC: 854 AN: 5178

South Asian (SAS) AF: 0.798 AC: 3848 AN: 4824

European-Finnish (FIN) AF: 0.591 AC: 6226 AN: 10538

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.703 AC: 47812 AN: 67986

Other (OTH) AF: 0.717 AC: 1510 AN: 2106

Alfa AF: 0.687 Hom.: 42168

Bravo AF: 0.695

Asia WGS AF: 0.540 AC: 1879 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	11
DANN	Benign	0.64
PhyloP100		0.20
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: rs1751492; hg19: chr1-65992625;