1-65591758-T-C

Variant names:

• chr1-65591758-T-C
• rs2154380
• NM_002303.6:c.495-899T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002303.6(LEPR):​c.495-899T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.503 in 151,790 control chromosomes in the GnomAD database, including 20,016 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 0.50 (20016 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0110
• Publications: 11 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.857 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	NM_002303.6	MANE Select	c.495-899T>C		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.495-899T>C		intron	N/A	NP_001003680.1
	LEPR	NM_001198687.2		c.495-899T>C		intron	N/A	NP_001185616.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.495-899T>C		intron	N/A	ENSP00000330393.7
	LEPR	ENST00000371059.7	TSL:1	c.495-899T>C		intron	N/A	ENSP00000360098.3
	LEPR	ENST00000344610.12	TSL:1	c.495-899T>C		intron	N/A	ENSP00000340884.8

Frequencies

GnomAD3 genomes AF: 0.503 AC: 76268 AN: 151672 Hom.: 19984 Cov.: 32

Gnomad AFR AF: 0.554

Gnomad AMI AF: 0.272

Gnomad AMR AF: 0.440

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.879

Gnomad SAS AF: 0.491

Gnomad FIN AF: 0.595

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.469

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

GnomAD4 genome AF: 0.503 AC: 76347 AN: 151790 Hom.: 20016 Cov.: 32 AF XY: 0.509 AC XY: 37786 AN XY: 74188

African (AFR) AF: 0.554 AC: 22961 AN: 41434

American (AMR) AF: 0.441 AC: 6714 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1450 AN: 3466

East Asian (EAS) AF: 0.878 AC: 4548 AN: 5178

South Asian (SAS) AF: 0.489 AC: 2360 AN: 4824

European-Finnish (FIN) AF: 0.595 AC: 6268 AN: 10536

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30692 AN: 67796

Other (OTH) AF: 0.476 AC: 1004 AN: 2110

Alfa AF: 0.455 Hom.: 47532

Bravo AF: 0.493

Asia WGS AF: 0.681 AC: 2348 AN: 3452

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.4
DANN	Benign	0.63
PhyloP100		-0.011
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: rs2154380; hg19: chr1-66057441;