1-65427205-C-A

Position:

• chr1-65427205-C-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+1827C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.693 in 152,060 control chromosomes in the GnomAD database, including 37,629 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 0.69 (37629 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.152

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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPR	NM_002303.6	c.-21+1827C>A		intron_variant		ENST00000349533.11
LEPROT	NM_017526.5	c.92+1827C>A		intron_variant		ENST00000371065.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPR	ENST00000349533.11	c.-21+1827C>A		intron_variant		1	NM_002303.6	P4
LEPROT	ENST00000371065.9	c.92+1827C>A		intron_variant		1	NM_017526.5	P1

Frequencies

GnomAD3 genomes AF: 0.693 AC: 105333 AN: 151938 Hom.: 37604 Cov.: 32

Gnomad AFR AF: 0.815

Gnomad AMI AF: 0.679

Gnomad AMR AF: 0.676

Gnomad ASJ AF: 0.776

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.704

Gnomad FIN AF: 0.551

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.677

Gnomad OTH AF: 0.701

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

GnomAD4 genome AF: 0.693 AC: 105410 AN: 152060 Hom.: 37629 Cov.: 32 AF XY: 0.684 AC XY: 50826 AN XY: 74302

Gnomad4 AFR AF: 0.815

Gnomad4 AMR AF: 0.675

Gnomad4 ASJ AF: 0.776

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.703

Gnomad4 FIN AF: 0.551

Gnomad4 NFE AF: 0.677

Gnomad4 OTH AF: 0.701

Alfa AF: 0.657 Hom.: 5251

Bravo AF: 0.705

Asia WGS AF: 0.491 AC: 1710 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.97
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: rs9436299; hg19: chr1-65892888;