rs7883

chr1-65432186-G-A

Variant summary

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

The NM_017526.5(LEPROT):c.*267G>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 0.0587 in 1,110,814 control chromosomes in the GnomAD database, including 4,451 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 0.13 (2371 hom., cov: 32)
  • Exomes 𝑓: 0.048 (2080 hom.)
• Consequence: LEPROT NM_017526.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.968

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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPROT	NM_017526.5	c.*267G>A		3_prime_UTR_variant	4/4	ENST00000371065.9
LEPR	NM_002303.6	c.-21+6808G>A		intron_variant		ENST00000349533.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPROT	ENST00000371065.9	c.*267G>A		3_prime_UTR_variant	4/4	1	NM_017526.5	P1
LEPR	ENST00000349533.11	c.-21+6808G>A		intron_variant		1	NM_002303.6	P4

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19508 AN: 151922 Hom.: 2365 Cov.: 32

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0621

Gnomad ASJ AF: 0.0631

Gnomad EAS AF: 0.0266

Gnomad SAS AF: 0.0968

Gnomad FIN AF: 0.0705

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0502

Gnomad OTH AF: 0.115

GnomAD4 exome AF: 0.0476 AC: 45652 AN: 958774 Hom.: 2080 Cov.: 30 AF XY: 0.0478 AC XY: 21600 AN XY: 451950

Gnomad4 AFR exome AF: 0.339

Gnomad4 AMR exome AF: 0.0565

Gnomad4 ASJ exome AF: 0.0613

Gnomad4 EAS exome AF: 0.0317

Gnomad4 SAS exome AF: 0.0875

Gnomad4 FIN exome AF: 0.0674

Gnomad4 NFE exome AF: 0.0388

Gnomad4 OTH exome AF: 0.0603

GnomAD4 genome AF: 0.129 AC: 19541 AN: 152040 Hom.: 2371 Cov.: 32 AF XY: 0.127 AC XY: 9447 AN XY: 74328

Gnomad4 AFR AF: 0.321

Gnomad4 AMR AF: 0.0618

Gnomad4 ASJ AF: 0.0631

Gnomad4 EAS AF: 0.0265

Gnomad4 SAS AF: 0.0959

Gnomad4 FIN AF: 0.0705

Gnomad4 NFE AF: 0.0502

Gnomad4 OTH AF: 0.115

Alfa AF: 0.0790 Hom.: 404

Bravo AF: 0.134

Asia WGS AF: 0.0850 AC: 294 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.024
Dann	Benign	0.55

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: rs7883; hg19: chr1-65897869; COSMIC: COSV105239700; COSMIC: COSV105239700;