chr1-65555668-A-G

Variant names:

• chr1-65555668-A-G
• rs1409802
• NM_002303.6:c.-20-9878A>G

Variant summary

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

The NM_002303.6(LEPR):​c.-20-9878A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.739 in 152,066 control chromosomes in the GnomAD database, including 42,603 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 0.74 (42603 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.20
• Publications: 6 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.813 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	NM_002303.6	MANE Select	c.-20-9878A>G		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.-20-9878A>G		intron	N/A	NP_001003680.1	P48357-3
	LEPR	NM_001198687.2		c.-20-9878A>G		intron	N/A	NP_001185616.1	P48357-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.-20-9878A>G		intron	N/A	ENSP00000330393.7	P48357-1
	LEPR	ENST00000371059.7	TSL:1	c.-20-9878A>G		intron	N/A	ENSP00000360098.3	P48357-3
	LEPR	ENST00000344610.12	TSL:1	c.-20-9878A>G		intron	N/A	ENSP00000340884.8	P48357-4

Frequencies

GnomAD3 genomes AF: 0.739 AC: 112284 AN: 151948 Hom.: 42558 Cov.: 32

Gnomad AFR AF: 0.820

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.744

Gnomad ASJ AF: 0.854

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.827

Gnomad FIN AF: 0.612

Gnomad MID AF: 0.899

Gnomad NFE AF: 0.735

Gnomad OTH AF: 0.754

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

GnomAD4 genome AF: 0.739 AC: 112383 AN: 152066 Hom.: 42603 Cov.: 32 AF XY: 0.734 AC XY: 54543 AN XY: 74344

African (AFR) AF: 0.820 AC: 34037 AN: 41492

American (AMR) AF: 0.744 AC: 11367 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.854 AC: 2963 AN: 3468

East Asian (EAS) AF: 0.198 AC: 1024 AN: 5168

South Asian (SAS) AF: 0.826 AC: 3985 AN: 4824

European-Finnish (FIN) AF: 0.612 AC: 6460 AN: 10550

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.735 AC: 49967 AN: 67960

Other (OTH) AF: 0.750 AC: 1584 AN: 2112

Alfa AF: 0.760 Hom.: 7855

Bravo AF: 0.748

Asia WGS AF: 0.582 AC: 2027 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.53
DANN	Benign	0.72
PhyloP100		-1.2
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: rs1409802; hg19: chr1-66021351; COSMIC: COSV60763341;