NM_002303.6:c.-20-42736C>T

Variant names:

• chr1-65522810-C-T
• rs1171279
• NM_002303.6:c.-20-42736C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_002303.6(LEPR):​c.-20-42736C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 150,054 control chromosomes in the GnomAD database, including 13,133 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 0.38 (13133 hom., cov: 31)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.857
• Publications: 17 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.-20-42736C>T		intron_variant	Intron 2 of 19	ENST00000349533.11	NP_002294.2
LEPR	NM_001003680.3	c.-20-42736C>T		intron_variant	Intron 2 of 19		NP_001003680.1
LEPR	NM_001003679.3	c.-20-42736C>T		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.-20-42736C>T		intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7
LEPR	ENST00000371059.7	c.-20-42736C>T		intron_variant	Intron 2 of 19	1		ENSP00000360098.3
LEPR	ENST00000371060.7	c.-20-42736C>T		intron_variant	Intron 2 of 19	1		ENSP00000360099.3

Frequencies

GnomAD3 genomes AF: 0.379 AC: 56909 AN: 149964 Hom.: 13100 Cov.: 31

Gnomad AFR AF: 0.636

Gnomad AMI AF: 0.410

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.579

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.369

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

GnomAD4 genome AF: 0.380 AC: 56991 AN: 150054 Hom.: 13133 Cov.: 31 AF XY: 0.380 AC XY: 27767 AN XY: 73118

African (AFR) AF: 0.636 AC: 26188 AN: 41158

American (AMR) AF: 0.342 AC: 5145 AN: 15022

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 1469 AN: 3462

East Asian (EAS) AF: 0.108 AC: 553 AN: 5142

South Asian (SAS) AF: 0.579 AC: 2759 AN: 4762

European-Finnish (FIN) AF: 0.177 AC: 1704 AN: 9638

Middle Eastern (MID) AF: 0.490 AC: 140 AN: 286

European-Non Finnish (NFE) AF: 0.265 AC: 17888 AN: 67588

Other (OTH) AF: 0.370 AC: 773 AN: 2088

Alfa AF: 0.310 Hom.: 5290

Bravo AF: 0.392

Asia WGS AF: 0.396 AC: 1379 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.64
PhyloP100		0.86
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: rs1171279; hg19: chr1-65988493;