1-65609453-C-T

Variant names:

• chr1-65609453-C-T
• rs11801408
• NM_002303.6:c.1753-494C>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.1753-494C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 152,096 control chromosomes in the GnomAD database, including 5,657 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 0.25 (5657 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.14
• Publications: 9 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.39 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.1753-494C>T		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.1753-494C>T		intron	N/A	NP_001003680.1	P48357-3
	LEPR	NM_001198687.2		c.1753-494C>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.1753-494C>T		intron	N/A	ENSP00000330393.7	P48357-1
	LEPR	ENST00000371059.7	TSL:1	c.1753-494C>T		intron	N/A	ENSP00000360098.3	P48357-3
	LEPR	ENST00000344610.12	TSL:1	c.1753-494C>T		intron	N/A	ENSP00000340884.8	P48357-4

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38299 AN: 151978 Hom.: 5634 Cov.: 32

Gnomad AFR AF: 0.395

Gnomad AMI AF: 0.264

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.290

Gnomad EAS AF: 0.0912

Gnomad SAS AF: 0.333

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.233

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

GnomAD4 genome AF: 0.252 AC: 38367 AN: 152096 Hom.: 5657 Cov.: 32 AF XY: 0.251 AC XY: 18693 AN XY: 74372

African (AFR) AF: 0.395 AC: 16396 AN: 41460

American (AMR) AF: 0.240 AC: 3668 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 1006 AN: 3472

East Asian (EAS) AF: 0.0912 AC: 471 AN: 5166

South Asian (SAS) AF: 0.332 AC: 1603 AN: 4824

European-Finnish (FIN) AF: 0.144 AC: 1527 AN: 10576

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.189 AC: 12867 AN: 67996

Other (OTH) AF: 0.236 AC: 498 AN: 2112

Alfa AF: 0.190 Hom.: 2472

Bravo AF: 0.259

Asia WGS AF: 0.245 AC: 850 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.025
DANN	Benign	0.83
PhyloP100		-3.1
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: rs11801408; hg19: chr1-66075136; COSMIC: COSV60750065;