rs6669117

Variant names:

• chr1-65595389-T-C
• rs6669117
• NM_002303.6:c.704-1059T>C

Variant summary

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

The NM_002303.6(LEPR):​c.704-1059T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.503 in 151,898 control chromosomes in the GnomAD database, including 20,012 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 (20012 hom., cov: 31)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.692
• Publications: 6 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.858 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.704-1059T>C		intron_variant	Intron 6 of 19	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.704-1059T>C		intron_variant	Intron 6 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76266 AN: 151780 Hom.: 19980 Cov.: 31

Gnomad AFR AF: 0.554

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.440

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.880

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.595

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.452

Gnomad OTH AF: 0.470

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

GnomAD4 genome AF: 0.503 AC: 76345 AN: 151898 Hom.: 20012 Cov.: 31 AF XY: 0.509 AC XY: 37785 AN XY: 74260

African (AFR) AF: 0.554 AC: 22944 AN: 41418

American (AMR) AF: 0.441 AC: 6716 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 1450 AN: 3464

East Asian (EAS) AF: 0.880 AC: 4542 AN: 5164

South Asian (SAS) AF: 0.486 AC: 2339 AN: 4810

European-Finnish (FIN) AF: 0.595 AC: 6294 AN: 10580

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

European-Non Finnish (NFE) AF: 0.452 AC: 30710 AN: 67914

Other (OTH) AF: 0.476 AC: 1000 AN: 2100

Alfa AF: 0.473 Hom.: 4127

Bravo AF: 0.493

Asia WGS AF: 0.678 AC: 2354 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.9
DANN	Benign	0.85
PhyloP100		0.69
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: rs6669117; hg19: chr1-66061072;