chr1-65430244-T-C

Position:

• chr1-65430244-T-C

Variant summary

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

The NM_002303.6(LEPR):​c.-21+4866T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 413,756 control chromosomes in the GnomAD database, including 14,292 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 0.28 (6539 hom., cov: 32)
  • Exomes 𝑓: 0.23 (7753 hom.)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0960

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=-0.67).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LEPR	NM_002303.6	c.-21+4866T>C		intron_variant		ENST00000349533.11	NP_002294.2
LEPROT	NM_017526.5	c.279+196T>C		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+4866T>C		intron_variant		1	NM_002303.6	ENSP00000330393	P4
LEPROT	ENST00000371065.9	c.279+196T>C		intron_variant		1	NM_017526.5	ENSP00000360104	P1

Frequencies

GnomAD3 genomes AF: 0.284 AC: 43099 AN: 151988 Hom.: 6530 Cov.: 32

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.275

Gnomad ASJ AF: 0.260

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.252

GnomAD4 exome AF: 0.233 AC: 61001 AN: 261650 Hom.: 7753 Cov.: 4 AF XY: 0.236 AC XY: 31827 AN XY: 134732

Gnomad4 AFR exome AF: 0.387

Gnomad4 AMR exome AF: 0.261

Gnomad4 ASJ exome AF: 0.254

Gnomad4 EAS exome AF: 0.0739

Gnomad4 SAS exome AF: 0.309

Gnomad4 FIN exome AF: 0.167

Gnomad4 NFE exome AF: 0.248

Gnomad4 OTH exome AF: 0.251

GnomAD4 genome AF: 0.284 AC: 43134 AN: 152106 Hom.: 6539 Cov.: 32 AF XY: 0.279 AC XY: 20784 AN XY: 74366

Gnomad4 AFR AF: 0.393

Gnomad4 AMR AF: 0.275

Gnomad4 ASJ AF: 0.260

Gnomad4 EAS AF: 0.118

Gnomad4 SAS AF: 0.318

Gnomad4 FIN AF: 0.155

Gnomad4 NFE AF: 0.250

Gnomad4 OTH AF: 0.254

Alfa AF: 0.253 Hom.: 8452

Bravo AF: 0.295

Asia WGS AF: 0.224 AC: 783 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	9.4
DANN	Benign	0.86

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: rs9436301; hg19: chr1-65895927;