rs1180445

Variant names:

• chr1-65517236-T-C
• rs1180445
• NM_002303.6:c.-20-48310T>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.-20-48310T>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 152,182 control chromosomes in the GnomAD database, including 3,591 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 (3591 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.106
• Publications: 4 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.-20-48310T>C		intron_variant	Intron 2 of 19	ENST00000349533.11	NP_002294.2
LEPR	NM_001003680.3	c.-20-48310T>C		intron_variant	Intron 2 of 19		NP_001003680.1
LEPR	NM_001003679.3	c.-20-48310T>C		intron_variant	Intron 2 of 19		NP_001003679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.-20-48310T>C		intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7
LEPR	ENST00000371059.7	c.-20-48310T>C		intron_variant	Intron 2 of 19	1		ENSP00000360098.3
LEPR	ENST00000371060.7	c.-20-48310T>C		intron_variant	Intron 2 of 19	1		ENSP00000360099.3

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31222 AN: 152064 Hom.: 3584 Cov.: 32

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.0451

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.0783

Gnomad MID AF: 0.344

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.212

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

GnomAD4 genome AF: 0.205 AC: 31251 AN: 152182 Hom.: 3591 Cov.: 32 AF XY: 0.204 AC XY: 15162 AN XY: 74410

African (AFR) AF: 0.279 AC: 11597 AN: 41510

American (AMR) AF: 0.236 AC: 3611 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 882 AN: 3472

East Asian (EAS) AF: 0.0452 AC: 234 AN: 5182

South Asian (SAS) AF: 0.280 AC: 1347 AN: 4812

European-Finnish (FIN) AF: 0.0783 AC: 831 AN: 10614

Middle Eastern (MID) AF: 0.336 AC: 98 AN: 292

European-Non Finnish (NFE) AF: 0.175 AC: 11881 AN: 67978

Other (OTH) AF: 0.211 AC: 445 AN: 2114

Alfa AF: 0.198 Hom.: 425

Bravo AF: 0.219

Asia WGS AF: 0.177 AC: 622 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.76
DANN	Benign	0.56
PhyloP100		-0.11
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: rs1180445; hg19: chr1-65982919;