rs3762274

Variant names:

• chr1-65598430-T-C
• rs3762274
• NM_002303.6:c.850-230T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-65598430-T-C
• chr1-65598430-T-A
• chr1-65598430-T-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.850-230T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.467 in 151,858 control chromosomes in the GnomAD database, including 17,765 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.47 (17765 hom., cov: 31)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0690
• Publications: 14 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=-0.91).
• BP6: Variant 1-65598430-T-C is Benign according to our data. Variant chr1-65598430-T-C is described in ClinVar as Benign. ClinVar VariationId is 1235525.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.862 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.850-230T>C		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.850-230T>C		intron	N/A	NP_001003680.1	P48357-3
	LEPR	NM_001198687.2		c.850-230T>C		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.850-230T>C		intron	N/A	ENSP00000330393.7	P48357-1
	LEPR	ENST00000371059.7	TSL:1	c.850-230T>C		intron	N/A	ENSP00000360098.3	P48357-3
	LEPR	ENST00000344610.12	TSL:1	c.850-230T>C		intron	N/A	ENSP00000340884.8	P48357-4

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70755 AN: 151740 Hom.: 17731 Cov.: 31

Gnomad AFR AF: 0.557

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.415

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.883

Gnomad SAS AF: 0.465

Gnomad FIN AF: 0.559

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.437

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

GnomAD4 genome AF: 0.467 AC: 70845 AN: 151858 Hom.: 17765 Cov.: 31 AF XY: 0.475 AC XY: 35220 AN XY: 74222

African (AFR) AF: 0.557 AC: 23039 AN: 41372

American (AMR) AF: 0.415 AC: 6342 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 1405 AN: 3462

East Asian (EAS) AF: 0.883 AC: 4568 AN: 5174

South Asian (SAS) AF: 0.463 AC: 2231 AN: 4816

European-Finnish (FIN) AF: 0.559 AC: 5897 AN: 10544

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.385 AC: 26174 AN: 67908

Other (OTH) AF: 0.444 AC: 938 AN: 2112

Alfa AF: 0.435 Hom.: 2277

Bravo AF: 0.461

Asia WGS AF: 0.678 AC: 2354 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	-0.91
CADD	Benign	2.6
DANN	Benign	0.52
PhyloP100		0.069
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: rs3762274; hg19: chr1-66064113;