rs7529650

Positions:

• chr1-65475849-G-A
• chr1-65475849-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.-21+50471G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 151,324 control chromosomes in the GnomAD database, including 20,125 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 0.50 (20125 hom., cov: 28)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.708

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.587 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPR	NM_002303.6	c.-21+50471G>A		intron_variant		ENST00000349533.11
LEPR	NM_001003679.3	c.-21+50471G>A		intron_variant
LEPR	NM_001003680.3	c.-21+50471G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPR	ENST00000349533.11	c.-21+50471G>A		intron_variant		1	NM_002303.6	P4
LEPR	ENST00000371059.7	c.-21+50471G>A		intron_variant		1
LEPR	ENST00000371060.7	c.-21+50471G>A		intron_variant		1		A1

Frequencies

GnomAD3 genomes AF: 0.502 AC: 75855 AN: 151206 Hom.: 20124 Cov.: 28

Gnomad AFR AF: 0.366

Gnomad AMI AF: 0.596

Gnomad AMR AF: 0.561

Gnomad ASJ AF: 0.647

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.471

Gnomad MID AF: 0.691

Gnomad NFE AF: 0.592

Gnomad OTH AF: 0.530

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

GnomAD4 genome AF: 0.501 AC: 75877 AN: 151324 Hom.: 20125 Cov.: 28 AF XY: 0.496 AC XY: 36645 AN XY: 73892

Gnomad4 AFR AF: 0.366

Gnomad4 AMR AF: 0.561

Gnomad4 ASJ AF: 0.647

Gnomad4 EAS AF: 0.116

Gnomad4 SAS AF: 0.535

Gnomad4 FIN AF: 0.471

Gnomad4 NFE AF: 0.592

Gnomad4 OTH AF: 0.529

Alfa AF: 0.536 Hom.: 2712

Bravo AF: 0.503

Asia WGS AF: 0.331 AC: 1155 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.54
DANN	Benign	0.64

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: rs7529650; hg19: chr1-65941532;