rs4655802

Variant names:

• chr1-65422548-G-A
• rs4655802
• NM_002303.6:c.-97+1808G>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.-97+1808G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.61 in 152,042 control chromosomes in the GnomAD database, including 28,531 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 0.61 (28531 hom., cov: 33)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.74
• Publications: 19 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]

LEPROT (HGNC:29477): (leptin receptor overlapping transcript) LEPROT is associated with the Golgi complex and endosomes and has a role in cell surface expression of growth hormone receptor (GHR; MIM 600946) and leptin receptor (OBR, or LEPR; MIM 601007), thereby altering receptor-mediated cell signaling (Couturier et al., 2007 [PubMed 18042720]; Touvier et al., 2009 [PubMed 19907080]).[supplied by OMIM, Jul 2010]

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 (EAS) allele frequency at 95% confidence interval = 0.84 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.-97+1808G>A		intron	N/A	NP_002294.2
	LEPROT	NM_017526.5	MANE Select	c.16+1808G>A		intron	N/A	NP_059996.1
	LEPR	NM_001003680.3		c.-97+1808G>A		intron	N/A	NP_001003680.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.-97+1808G>A		intron	N/A	ENSP00000330393.7
	LEPROT	ENST00000371065.9	TSL:1 MANE Select	c.16+1808G>A		intron	N/A	ENSP00000360104.4
	LEPR	ENST00000371059.7	TSL:1	c.-97+1808G>A		intron	N/A	ENSP00000360098.3

Frequencies

GnomAD3 genomes AF: 0.610 AC: 92705 AN: 151926 Hom.: 28484 Cov.: 33

Gnomad AFR AF: 0.626

Gnomad AMI AF: 0.609

Gnomad AMR AF: 0.566

Gnomad ASJ AF: 0.587

Gnomad EAS AF: 0.860

Gnomad SAS AF: 0.672

Gnomad FIN AF: 0.589

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.592

Gnomad OTH AF: 0.612

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

GnomAD4 genome AF: 0.610 AC: 92810 AN: 152042 Hom.: 28531 Cov.: 33 AF XY: 0.612 AC XY: 45475 AN XY: 74306

African (AFR) AF: 0.626 AC: 25965 AN: 41452

American (AMR) AF: 0.566 AC: 8653 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.587 AC: 2036 AN: 3470

East Asian (EAS) AF: 0.861 AC: 4457 AN: 5178

South Asian (SAS) AF: 0.673 AC: 3241 AN: 4818

European-Finnish (FIN) AF: 0.589 AC: 6218 AN: 10564

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.592 AC: 40213 AN: 67966

Other (OTH) AF: 0.612 AC: 1295 AN: 2116

Alfa AF: 0.594 Hom.: 12919

Bravo AF: 0.607

Asia WGS AF: 0.712 AC: 2476 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.18
DANN	Benign	0.53
PhyloP100		-1.7
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: rs4655802; hg19: chr1-65888231;