chr1-65430878-G-A

Position:

• chr1-65430878-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002303.6(LEPR):​c.-21+5500G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 152,054 control chromosomes in the GnomAD database, including 5,604 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 0.26 (5604 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.441

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.381 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LEPR	NM_002303.6	c.-21+5500G>A		intron_variant		ENST00000349533.11	NP_002294.2
LEPROT	NM_017526.5	c.279+830G>A		intron_variant		ENST00000371065.9	NP_059996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.-21+5500G>A		intron_variant		1	NM_002303.6	ENSP00000330393	P4
LEPROT	ENST00000371065.9	c.279+830G>A		intron_variant		1	NM_017526.5	ENSP00000360104	P1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39116 AN: 151936 Hom.: 5595 Cov.: 32

Gnomad AFR AF: 0.386

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.233

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

GnomAD4 genome AF: 0.257 AC: 39152 AN: 152054 Hom.: 5604 Cov.: 32 AF XY: 0.254 AC XY: 18870 AN XY: 74332

Gnomad4 AFR AF: 0.386

Gnomad4 AMR AF: 0.257

Gnomad4 ASJ AF: 0.247

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.311

Gnomad4 FIN AF: 0.108

Gnomad4 NFE AF: 0.209

Gnomad4 OTH AF: 0.234

Alfa AF: 0.227 Hom.: 1086

Bravo AF: 0.273

Asia WGS AF: 0.218 AC: 762 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.1
DANN	Benign	0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs9436302; hg19: chr1-65896561;