1-65589312-T-G

Variant names:

• chr1-65589312-T-G
• rs6696954
• NM_002303.6:c.495-3345T>G

Variant summary

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

The NM_002303.6(LEPR):​c.495-3345T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.667 in 151,810 control chromosomes in the GnomAD database, including 34,118 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 0.67 (34118 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.325
• Publications: 7 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=-1.02).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.903 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.495-3345T>G		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.495-3345T>G		intron_variant	Intron 5 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.667 AC: 101171 AN: 151692 Hom.: 34076 Cov.: 32

Gnomad AFR AF: 0.609

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.683

Gnomad ASJ AF: 0.703

Gnomad EAS AF: 0.925

Gnomad SAS AF: 0.673

Gnomad FIN AF: 0.728

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.669

Gnomad OTH AF: 0.667

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

GnomAD4 genome AF: 0.667 AC: 101265 AN: 151810 Hom.: 34118 Cov.: 32 AF XY: 0.671 AC XY: 49794 AN XY: 74208

African (AFR) AF: 0.609 AC: 25217 AN: 41376

American (AMR) AF: 0.683 AC: 10411 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.703 AC: 2435 AN: 3466

East Asian (EAS) AF: 0.925 AC: 4791 AN: 5182

South Asian (SAS) AF: 0.672 AC: 3229 AN: 4806

European-Finnish (FIN) AF: 0.728 AC: 7700 AN: 10578

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.669 AC: 45420 AN: 67852

Other (OTH) AF: 0.671 AC: 1407 AN: 2098

Alfa AF: 0.662 Hom.: 4141

Bravo AF: 0.657

Asia WGS AF: 0.801 AC: 2777 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.0
DANN	Benign	0.31
PhyloP100		-0.33
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: rs6696954; hg19: chr1-66054995; COSMIC: COSV60749959;