rs1627238

Variant names:

• chr1-65520396-G-A
• rs1627238
• NM_002303.6:c.-20-45150G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-65520396-G-A
• chr1-65520396-G-T

Variant summary

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

The NM_002303.6(LEPR):​c.-20-45150G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 151,994 control chromosomes in the GnomAD database, including 6,090 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 0.25 (6090 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.793
• Publications: 8 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=-0.77).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.-20-45150G>A		intron_variant	Intron 2 of 19	ENST00000349533.11	NP_002294.2
LEPR	NM_001003680.3	c.-20-45150G>A		intron_variant	Intron 2 of 19		NP_001003680.1
LEPR	NM_001003679.3	c.-20-45150G>A		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.-20-45150G>A		intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7
LEPR	ENST00000371059.7	c.-20-45150G>A		intron_variant	Intron 2 of 19	1		ENSP00000360098.3
LEPR	ENST00000371060.7	c.-20-45150G>A		intron_variant	Intron 2 of 19	1		ENSP00000360099.3

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38271 AN: 151876 Hom.: 6079 Cov.: 32

Gnomad AFR AF: 0.439

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.0447

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.0788

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.245

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

GnomAD4 genome AF: 0.252 AC: 38315 AN: 151994 Hom.: 6090 Cov.: 32 AF XY: 0.249 AC XY: 18501 AN XY: 74310

African (AFR) AF: 0.439 AC: 18188 AN: 41420

American (AMR) AF: 0.254 AC: 3880 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 943 AN: 3468

East Asian (EAS) AF: 0.0448 AC: 232 AN: 5178

South Asian (SAS) AF: 0.281 AC: 1351 AN: 4812

European-Finnish (FIN) AF: 0.0788 AC: 833 AN: 10570

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

European-Non Finnish (NFE) AF: 0.176 AC: 11949 AN: 67978

Other (OTH) AF: 0.243 AC: 512 AN: 2104

Alfa AF: 0.119 Hom.: 236

Bravo AF: 0.271

Asia WGS AF: 0.185 AC: 650 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.66
DANN	Benign	0.88
PhyloP100		-0.79
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: rs1627238; hg19: chr1-65986079;