1-65513597-T-C

Variant names:

• chr1-65513597-T-C
• rs11208659
• NM_002303.6:c.-20-51949T>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.-20-51949T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 152,156 control chromosomes in the GnomAD database, including 3,239 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 0.17 (3239 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.40
• Publications: 36 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=-0.57).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.346 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.-20-51949T>C		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.-20-51949T>C		intron	N/A	NP_001003680.1	P48357-3
	LEPR	NM_001003679.3		c.-20-51949T>C		intron	N/A	NP_001003679.1	P48357-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.-20-51949T>C		intron	N/A	ENSP00000330393.7	P48357-1
	LEPR	ENST00000371059.7	TSL:1	c.-20-51949T>C		intron	N/A	ENSP00000360098.3	P48357-3
	LEPR	ENST00000371060.7	TSL:1	c.-20-51949T>C		intron	N/A	ENSP00000360099.3	P48357-2

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25385 AN: 152038 Hom.: 3227 Cov.: 32

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.0635

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.0904

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0892

Gnomad OTH AF: 0.154

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

GnomAD4 genome AF: 0.167 AC: 25435 AN: 152156 Hom.: 3239 Cov.: 32 AF XY: 0.166 AC XY: 12350 AN XY: 74410

African (AFR) AF: 0.351 AC: 14546 AN: 41474

American (AMR) AF: 0.102 AC: 1561 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 595 AN: 3468

East Asian (EAS) AF: 0.0630 AC: 326 AN: 5172

South Asian (SAS) AF: 0.200 AC: 964 AN: 4822

European-Finnish (FIN) AF: 0.0904 AC: 959 AN: 10606

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.0892 AC: 6065 AN: 68004

Other (OTH) AF: 0.155 AC: 328 AN: 2112

Alfa AF: 0.120 Hom.: 4755

Bravo AF: 0.172

Asia WGS AF: 0.183 AC: 635 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	14
DANN	Benign	0.72
PhyloP100		1.4
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: rs11208659; hg19: chr1-65979280;