rs9436738

Positions:

• chr1-65422877-G-A
• chr1-65422877-G-C

Variant summary

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

The NM_002303.6(LEPR):​c.-97+2137G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 152,184 control chromosomes in the GnomAD database, including 1,267 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 (1267 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24

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 (NFE) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LEPR	NM_002303.6	c.-97+2137G>A		intron_variant		ENST00000349533.11	NP_002294.2
LEPROT	NM_017526.5	c.16+2137G>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.-97+2137G>A		intron_variant		1	NM_002303.6	ENSP00000330393	P4
LEPROT	ENST00000371065.9	c.16+2137G>A		intron_variant		1	NM_017526.5	ENSP00000360104	P1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19118 AN: 152066 Hom.: 1263 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.0994

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.00501

Gnomad SAS AF: 0.0886

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.128

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

GnomAD4 genome AF: 0.126 AC: 19152 AN: 152184 Hom.: 1267 Cov.: 32 AF XY: 0.123 AC XY: 9159 AN XY: 74394

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.0992

Gnomad4 ASJ AF: 0.138

Gnomad4 EAS AF: 0.00522

Gnomad4 SAS AF: 0.0885

Gnomad4 FIN AF: 0.123

Gnomad4 NFE AF: 0.137

Gnomad4 OTH AF: 0.126

Alfa AF: 0.131 Hom.: 275

Bravo AF: 0.124

Asia WGS AF: 0.0570 AC: 198 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	0.63
DANN	Benign	0.68

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: rs9436738; hg19: chr1-65888560;