rs3790439

Variant names:

• chr1-65619891-T-A
• rs3790439
• NM_002303.6:c.2396-37T>A

Your query was ambiguous. Multiple possible variants found:

• chr1-65619891-T-A
• chr1-65619891-T-C
• chr1-65619891-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002303.6(LEPR):​c.2396-37T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 1,471,512 control chromosomes in the GnomAD database, including 129,980 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (17196 hom., cov: 32)
  • Exomes 𝑓: 0.40 (112784 hom.)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.287
• 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-65619891-T-A is Benign according to our data. Variant chr1-65619891-T-A is described in ClinVar as Benign. ClinVar VariationId is 1262802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.848 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.2396-37T>A		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.2396-37T>A		intron	N/A	NP_001003680.1	P48357-3
	LEPR	NM_001198687.2		c.2396-37T>A		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.2396-37T>A		intron	N/A	ENSP00000330393.7	P48357-1
	LEPR	ENST00000371059.7	TSL:1	c.2396-37T>A		intron	N/A	ENSP00000360098.3	P48357-3
	LEPR	ENST00000344610.12	TSL:1	c.2396-37T>A		intron	N/A	ENSP00000340884.8	P48357-4

Frequencies

GnomAD3 genomes AF: 0.463 AC: 70321 AN: 151878 Hom.: 17159 Cov.: 32

Gnomad AFR AF: 0.549

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.376

Gnomad EAS AF: 0.870

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.491

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.436

GnomAD2 exomes AF: 0.463 AC: 113631 AN: 245322 AF XY: 0.455

Gnomad AFR exome AF: 0.556

Gnomad AMR exome AF: 0.514

Gnomad ASJ exome AF: 0.371

Gnomad EAS exome AF: 0.873

Gnomad FIN exome AF: 0.476

Gnomad NFE exome AF: 0.374

Gnomad OTH exome AF: 0.426

GnomAD4 exome AF: 0.401 AC: 529394 AN: 1319516 Hom.: 112784 Cov.: 20 AF XY: 0.402 AC XY: 266761 AN XY: 664218

African (AFR) AF: 0.548 AC: 16677 AN: 30410

American (AMR) AF: 0.506 AC: 22403 AN: 44232

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 9418 AN: 25116

East Asian (EAS) AF: 0.868 AC: 33565 AN: 38650

South Asian (SAS) AF: 0.462 AC: 38176 AN: 82640

European-Finnish (FIN) AF: 0.472 AC: 25062 AN: 53048

Middle Eastern (MID) AF: 0.362 AC: 1911 AN: 5274

European-Non Finnish (NFE) AF: 0.365 AC: 359243 AN: 984898

Other (OTH) AF: 0.415 AC: 22939 AN: 55248

GnomAD4 genome AF: 0.463 AC: 70414 AN: 151996 Hom.: 17196 Cov.: 32 AF XY: 0.470 AC XY: 34947 AN XY: 74286

African (AFR) AF: 0.550 AC: 22785 AN: 41462

American (AMR) AF: 0.484 AC: 7395 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.376 AC: 1303 AN: 3468

East Asian (EAS) AF: 0.869 AC: 4498 AN: 5176

South Asian (SAS) AF: 0.462 AC: 2227 AN: 4820

European-Finnish (FIN) AF: 0.491 AC: 5169 AN: 10536

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.378 AC: 25690 AN: 67946

Other (OTH) AF: 0.443 AC: 937 AN: 2116

Alfa AF: 0.403 Hom.: 2328

Bravo AF: 0.466

Asia WGS AF: 0.625 AC: 2165 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.9
DANN	Benign	0.49
PhyloP100		-0.29
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: rs3790439; hg19: chr1-66085574; COSMIC: COSV60750189; COSMIC: COSV60750189;