rs1022981

Variant names:

• chr1-65534351-G-A
• rs1022981
• NM_002303.6:c.-20-31195G>A

Variant summary

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

The NM_002303.6(LEPR):​c.-20-31195G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.727 in 152,024 control chromosomes in the GnomAD database, including 41,284 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 0.73 (41284 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0110
• Publications: 13 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=-0.95).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.803 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.-20-31195G>A		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.-20-31195G>A		intron	N/A	NP_001003680.1
	LEPR	NM_001198687.2		c.-21+8533G>A		intron	N/A	NP_001185616.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.-20-31195G>A		intron	N/A	ENSP00000330393.7
	LEPR	ENST00000371059.7	TSL:1	c.-20-31195G>A		intron	N/A	ENSP00000360098.3
	LEPR	ENST00000344610.12	TSL:1	c.-21+8533G>A		intron	N/A	ENSP00000340884.8

Frequencies

GnomAD3 genomes AF: 0.727 AC: 110462 AN: 151906 Hom.: 41253 Cov.: 32

Gnomad AFR AF: 0.801

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.739

Gnomad ASJ AF: 0.843

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.825

Gnomad FIN AF: 0.597

Gnomad MID AF: 0.902

Gnomad NFE AF: 0.727

Gnomad OTH AF: 0.749

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

GnomAD4 genome AF: 0.727 AC: 110546 AN: 152024 Hom.: 41284 Cov.: 32 AF XY: 0.721 AC XY: 53559 AN XY: 74292

African (AFR) AF: 0.801 AC: 33235 AN: 41472

American (AMR) AF: 0.738 AC: 11279 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.843 AC: 2925 AN: 3468

East Asian (EAS) AF: 0.172 AC: 893 AN: 5178

South Asian (SAS) AF: 0.825 AC: 3976 AN: 4822

European-Finnish (FIN) AF: 0.597 AC: 6290 AN: 10532

Middle Eastern (MID) AF: 0.901 AC: 265 AN: 294

European-Non Finnish (NFE) AF: 0.727 AC: 49378 AN: 67952

Other (OTH) AF: 0.745 AC: 1573 AN: 2112

Alfa AF: 0.751 Hom.: 26479

Bravo AF: 0.736

Asia WGS AF: 0.564 AC: 1958 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.3
DANN	Benign	0.63
PhyloP100		-0.011
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: rs1022981; hg19: chr1-66000034;