NM_002303.6:c.703+253A>G

Variant names:

• chr1-65593118-A-G
• rs4655537
• NM_002303.6:c.703+253A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002303.6(LEPR):​c.703+253A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.651 in 151,906 control chromosomes in the GnomAD database, including 32,571 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.65 (32571 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.522
• Publications: 31 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 1-65593118-A-G is Benign according to our data. Variant chr1-65593118-A-G is described in ClinVar as Benign. ClinVar VariationId is 1286120.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.902 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002303.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	NM_002303.6	MANE Select	c.703+253A>G		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.703+253A>G		intron	N/A	NP_001003680.1	P48357-3
	LEPR	NM_001198687.2		c.703+253A>G		intron	N/A	NP_001185616.1	P48357-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.703+253A>G		intron	N/A	ENSP00000330393.7	P48357-1
	LEPR	ENST00000371059.7	TSL:1	c.703+253A>G		intron	N/A	ENSP00000360098.3	P48357-3
	LEPR	ENST00000344610.12	TSL:1	c.703+253A>G		intron	N/A	ENSP00000340884.8	P48357-4

Frequencies

GnomAD3 genomes AF: 0.651 AC: 98857 AN: 151788 Hom.: 32526 Cov.: 32

Gnomad AFR AF: 0.606

Gnomad AMI AF: 0.513

Gnomad AMR AF: 0.658

Gnomad ASJ AF: 0.686

Gnomad EAS AF: 0.924

Gnomad SAS AF: 0.668

Gnomad FIN AF: 0.725

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.644

Gnomad OTH AF: 0.642

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

GnomAD4 genome AF: 0.651 AC: 98959 AN: 151906 Hom.: 32571 Cov.: 32 AF XY: 0.656 AC XY: 48727 AN XY: 74242

African (AFR) AF: 0.607 AC: 25150 AN: 41446

American (AMR) AF: 0.658 AC: 10023 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.686 AC: 2378 AN: 3468

East Asian (EAS) AF: 0.924 AC: 4782 AN: 5176

South Asian (SAS) AF: 0.668 AC: 3222 AN: 4826

European-Finnish (FIN) AF: 0.725 AC: 7646 AN: 10550

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.644 AC: 43754 AN: 67904

Other (OTH) AF: 0.646 AC: 1360 AN: 2106

Alfa AF: 0.636 Hom.: 54133

Bravo AF: 0.640

Asia WGS AF: 0.795 AC: 2759 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.79
DANN	Benign	0.70
PhyloP100		-0.52
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: rs4655537; hg19: chr1-66058801; COSMIC: COSV60749969;