NM_002303.6:c.2674-4693G>A

Variant names:

• chr1-65631498-G-A
• rs1892535
• NM_002303.6:c.2674-4693G>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.2674-4693G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 147,946 control chromosomes in the GnomAD database, including 4,588 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 0.22 (4588 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.236
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.2674-4693G>A		intron_variant	Intron 19 of 19	ENST00000349533.11	NP_002294.2
LEPR	NM_001003679.3	c.2674-1654G>A		intron_variant	Intron 19 of 19		NP_001003679.1
LEPR	NM_001198689.2	c.2674-1654G>A		intron_variant	Intron 18 of 18		NP_001185618.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.2674-4693G>A		intron_variant	Intron 19 of 19	1	NM_002303.6	ENSP00000330393.7
LEPR	ENST00000371060.7	c.2674-1654G>A		intron_variant	Intron 19 of 19	1		ENSP00000360099.3
LEPR	ENST00000616738.4	c.2674-1654G>A		intron_variant	Intron 18 of 18	1		ENSP00000483390.1

Frequencies

GnomAD3 genomes AF: 0.218 AC: 32201 AN: 147840 Hom.: 4586 Cov.: 32

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.0663

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.0885

Gnomad EAS AF: 0.777

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.0584

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.208

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

GnomAD4 genome AF: 0.218 AC: 32222 AN: 147946 Hom.: 4588 Cov.: 32 AF XY: 0.227 AC XY: 16375 AN XY: 72168

African (AFR) AF: 0.161 AC: 6379 AN: 39510

American (AMR) AF: 0.251 AC: 3700 AN: 14740

Ashkenazi Jewish (ASJ) AF: 0.0885 AC: 299 AN: 3378

East Asian (EAS) AF: 0.777 AC: 4001 AN: 5150

South Asian (SAS) AF: 0.139 AC: 615 AN: 4440

European-Finnish (FIN) AF: 0.356 AC: 3702 AN: 10410

Middle Eastern (MID) AF: 0.0664 AC: 19 AN: 286

European-Non Finnish (NFE) AF: 0.194 AC: 13012 AN: 67094

Other (OTH) AF: 0.213 AC: 436 AN: 2048

Alfa AF: 0.204 Hom.: 1029

Bravo AF: 0.207

Asia WGS AF: 0.382 AC: 1326 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.6
DANN	Benign	0.20
PhyloP100		0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs1892535; hg19: chr1-66097181;