rs10749754

Variant names:

• chr1-65588957-G-A
• rs10749754
• NM_002303.6:c.495-3700G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002303.6(LEPR):​c.495-3700G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.492 in 151,908 control chromosomes in the GnomAD database, including 19,105 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 0.49 (19105 hom., cov: 33)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0990
• Publications: 10 publications found

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]

LEPR Gene-Disease associations (from GenCC):

• obesity due to leptin receptor gene deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.843 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.495-3700G>A		intron_variant	Intron 5 of 19	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.495-3700G>A		intron_variant	Intron 5 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74603 AN: 151790 Hom.: 19073 Cov.: 33

Gnomad AFR AF: 0.516

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.435

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.864

Gnomad SAS AF: 0.489

Gnomad FIN AF: 0.595

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.461

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

GnomAD4 genome AF: 0.492 AC: 74689 AN: 151908 Hom.: 19105 Cov.: 33 AF XY: 0.498 AC XY: 37005 AN XY: 74252

African (AFR) AF: 0.516 AC: 21404 AN: 41458

American (AMR) AF: 0.436 AC: 6644 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1447 AN: 3464

East Asian (EAS) AF: 0.864 AC: 4468 AN: 5172

South Asian (SAS) AF: 0.487 AC: 2350 AN: 4824

European-Finnish (FIN) AF: 0.595 AC: 6279 AN: 10550

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30748 AN: 67874

Other (OTH) AF: 0.468 AC: 987 AN: 2110

Alfa AF: 0.465 Hom.: 6537

Bravo AF: 0.480

Asia WGS AF: 0.674 AC: 2340 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.41
DANN	Benign	0.45
PhyloP100		-0.099
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10749754; hg19: chr1-66054640;