1-65578330-A-G

Variant names:

• chr1-65578330-A-G
• rs3790424
• NM_002303.6:c.494+5881A>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.494+5881A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 223,698 control chromosomes in the GnomAD database, including 11,995 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 0.30 (7878 hom., cov: 31)
  • Exomes 𝑓: 0.31 (4117 hom.)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.811
• 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: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000224570 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.81 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.494+5881A>G		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.494+5881A>G		intron	N/A	NP_001003680.1	P48357-3
	LEPR	NM_001198687.2		c.494+5881A>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.494+5881A>G		intron	N/A	ENSP00000330393.7	P48357-1
	LEPR	ENST00000371059.7	TSL:1	c.494+5881A>G		intron	N/A	ENSP00000360098.3	P48357-3
	LEPR	ENST00000344610.12	TSL:1	c.494+5881A>G		intron	N/A	ENSP00000340884.8	P48357-4

Frequencies

GnomAD3 genomes AF: 0.303 AC: 46063 AN: 151936 Hom.: 7866 Cov.: 31

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.291

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.831

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.279

GnomAD4 exome AF: 0.307 AC: 22029 AN: 71644 Hom.: 4117 Cov.: 0 AF XY: 0.292 AC XY: 12511 AN XY: 42792

African (AFR) AF: 0.302 AC: 615 AN: 2034

American (AMR) AF: 0.345 AC: 3105 AN: 9010

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 191 AN: 1004

East Asian (EAS) AF: 0.836 AC: 3441 AN: 4114

South Asian (SAS) AF: 0.184 AC: 1537 AN: 8368

European-Finnish (FIN) AF: 0.353 AC: 1985 AN: 5628

Middle Eastern (MID) AF: 0.0857 AC: 133 AN: 1552

European-Non Finnish (NFE) AF: 0.275 AC: 10204 AN: 37120

Other (OTH) AF: 0.291 AC: 818 AN: 2814

GnomAD4 genome AF: 0.303 AC: 46123 AN: 152054 Hom.: 7878 Cov.: 31 AF XY: 0.307 AC XY: 22811 AN XY: 74340

African (AFR) AF: 0.287 AC: 11911 AN: 41452

American (AMR) AF: 0.292 AC: 4460 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 594 AN: 3470

East Asian (EAS) AF: 0.831 AC: 4282 AN: 5154

South Asian (SAS) AF: 0.197 AC: 950 AN: 4826

European-Finnish (FIN) AF: 0.376 AC: 3979 AN: 10584

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.282 AC: 19148 AN: 67982

Other (OTH) AF: 0.282 AC: 595 AN: 2108

Alfa AF: 0.285 Hom.: 1700

Bravo AF: 0.301

Asia WGS AF: 0.436 AC: 1514 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.2
DANN	Benign	0.54
PhyloP100		-0.81
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: rs3790424; hg19: chr1-66044013;