rs12062820

Variant names:

• chr1-65504812-T-C
• rs12062820
• NM_002303.6:c.-20-60734T>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.-20-60734T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 152,070 control chromosomes in the GnomAD database, including 3,582 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 0.21 (3582 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40
• 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: 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 (SAS) allele frequency at 95% confidence interval = 0.274 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.-20-60734T>C		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.-20-60734T>C		intron	N/A	NP_001003680.1
	LEPR	NM_001003679.3		c.-20-60734T>C		intron	N/A	NP_001003679.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.-20-60734T>C		intron	N/A	ENSP00000330393.7
	LEPR	ENST00000371059.7	TSL:1	c.-20-60734T>C		intron	N/A	ENSP00000360098.3
	LEPR	ENST00000371060.7	TSL:1	c.-20-60734T>C		intron	N/A	ENSP00000360099.3

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31193 AN: 151952 Hom.: 3578 Cov.: 32

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.0450

Gnomad SAS AF: 0.285

Gnomad FIN AF: 0.0781

Gnomad MID AF: 0.341

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.211

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

GnomAD4 genome AF: 0.205 AC: 31215 AN: 152070 Hom.: 3582 Cov.: 32 AF XY: 0.204 AC XY: 15137 AN XY: 74324

African (AFR) AF: 0.279 AC: 11555 AN: 41454

American (AMR) AF: 0.236 AC: 3601 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 881 AN: 3470

East Asian (EAS) AF: 0.0451 AC: 234 AN: 5186

South Asian (SAS) AF: 0.286 AC: 1372 AN: 4800

European-Finnish (FIN) AF: 0.0781 AC: 827 AN: 10594

Middle Eastern (MID) AF: 0.332 AC: 97 AN: 292

European-Non Finnish (NFE) AF: 0.175 AC: 11881 AN: 67984

Other (OTH) AF: 0.210 AC: 443 AN: 2108

Alfa AF: 0.200 Hom.: 578

Bravo AF: 0.220

Asia WGS AF: 0.177 AC: 621 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.21
DANN	Benign	0.62
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: rs12062820; hg19: chr1-65970495;