rs3790439

Positions:

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

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: -0.287

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 1262802.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.848 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPR	NM_002303.6	c.2396-37T>A		intron_variant		ENST00000349533.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPR	ENST00000349533.11	c.2396-37T>A		intron_variant		1	NM_002303.6	P4

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

GnomAD3 exomes AF: 0.463 AC: 113631 AN: 245322 Hom.: 28495 AF XY: 0.455 AC XY: 60469 AN XY: 132776

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 SAS exome AF: 0.466

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

Gnomad4 AFR exome AF: 0.548

Gnomad4 AMR exome AF: 0.506

Gnomad4 ASJ exome AF: 0.375

Gnomad4 EAS exome AF: 0.868

Gnomad4 SAS exome AF: 0.462

Gnomad4 FIN exome AF: 0.472

Gnomad4 NFE exome AF: 0.365

Gnomad4 OTH exome AF: 0.415

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

Gnomad4 AFR AF: 0.550

Gnomad4 AMR AF: 0.484

Gnomad4 ASJ AF: 0.376

Gnomad4 EAS AF: 0.869

Gnomad4 SAS AF: 0.462

Gnomad4 FIN AF: 0.491

Gnomad4 NFE AF: 0.378

Gnomad4 OTH AF: 0.443

Alfa AF: 0.403 Hom.: 2328

Bravo AF: 0.466

Asia WGS AF: 0.625 AC: 2165 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.9
DANN	Benign	0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs3790439; hg19: chr1-66085574; COSMIC: COSV60750189; COSMIC: COSV60750189;