1-65609453-C-T

Position:

• chr1-65609453-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LEPR	NM_002303.6	c.1753-494C>T		intron_variant		ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.1753-494C>T		intron_variant		1	NM_002303.6	ENSP00000330393.7

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

Gnomad4 AFR AF: 0.395

Gnomad4 AMR AF: 0.240

Gnomad4 ASJ AF: 0.290

Gnomad4 EAS AF: 0.0912

Gnomad4 SAS AF: 0.332

Gnomad4 FIN AF: 0.144

Gnomad4 NFE AF: 0.189

Gnomad4 OTH AF: 0.236

Alfa AF: 0.185 Hom.: 1961

Bravo AF: 0.259

Asia WGS AF: 0.245 AC: 850 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.025
DANN	Benign	0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs11801408; hg19: chr1-66075136; COSMIC: COSV60750065;