1-65432298-G-A

Position:

• chr1-65432298-G-A

Variant summary

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

The ENST00000371065.9(LEPROT):​c.*379G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.362 in 993,224 control chromosomes in the GnomAD database, including 69,079 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 0.27 (7201 hom., cov: 31)
  • Exomes 𝑓: 0.38 (61878 hom.)
• Consequence: LEPROT ENST00000371065.9 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) 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
LEPROT	NM_017526.5	c.*379G>A		3_prime_UTR_variant	4/4	ENST00000371065.9	NP_059996.1
LEPR	NM_002303.6	c.-21+6920G>A		intron_variant		ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LEPROT	ENST00000371065.9	c.*379G>A		3_prime_UTR_variant	4/4	1	NM_017526.5	ENSP00000360104	P1
LEPR	ENST00000349533.11	c.-21+6920G>A		intron_variant		1	NM_002303.6	ENSP00000330393	P4

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41344 AN: 151872 Hom.: 7204 Cov.: 31

Gnomad AFR AF: 0.0734

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.397

Gnomad EAS AF: 0.0249

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.318

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.320

GnomAD4 exome AF: 0.378 AC: 318068 AN: 841234 Hom.: 61878 Cov.: 32 AF XY: 0.379 AC XY: 147706 AN XY: 389248

Gnomad4 AFR exome AF: 0.0468

Gnomad4 AMR exome AF: 0.332

Gnomad4 ASJ exome AF: 0.406

Gnomad4 EAS exome AF: 0.0230

Gnomad4 SAS exome AF: 0.226

Gnomad4 FIN exome AF: 0.348

Gnomad4 NFE exome AF: 0.392

Gnomad4 OTH exome AF: 0.341

GnomAD4 genome AF: 0.272 AC: 41334 AN: 151990 Hom.: 7201 Cov.: 31 AF XY: 0.266 AC XY: 19777 AN XY: 74280

Gnomad4 AFR AF: 0.0732

Gnomad4 AMR AF: 0.335

Gnomad4 ASJ AF: 0.397

Gnomad4 EAS AF: 0.0252

Gnomad4 SAS AF: 0.216

Gnomad4 FIN AF: 0.318

Gnomad4 NFE AF: 0.385

Gnomad4 OTH AF: 0.317

Alfa AF: 0.353 Hom.: 6830

Bravo AF: 0.269

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.2
DANN	Benign	0.73

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: rs1045895; hg19: chr1-65897981;