rs3790438

chr1-65619842-T-Achr1-65619842-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.2396-86T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 1,018,134 control chromosomes in the GnomAD database, including 15,244 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.17 (2485 hom., cov: 32)
  • Exomes 𝑓: 0.17 (12759 hom.)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.902

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=-0.86).
• BP6: Variant 1-65619842-T-A is Benign according to our data. Variant chr1-65619842-T-A is described in ClinVar as [Benign]. Clinvar id is 1247474.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPR	NM_002303.6	c.2396-86T>A		intron_variant		ENST00000349533.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPR	ENST00000349533.11	c.2396-86T>A		intron_variant		1	NM_002303.6	P4

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26614 AN: 152082 Hom.: 2485 Cov.: 32

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.0600

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.179

GnomAD4 exome AF: 0.168 AC: 145642 AN: 865934 Hom.: 12759 AF XY: 0.168 AC XY: 75824 AN XY: 450020

Gnomad4 AFR exome AF: 0.194

Gnomad4 AMR exome AF: 0.175

Gnomad4 ASJ exome AF: 0.218

Gnomad4 EAS exome AF: 0.0821

Gnomad4 SAS exome AF: 0.146

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.176

Gnomad4 OTH exome AF: 0.172

GnomAD4 genome AF: 0.175 AC: 26627 AN: 152200 Hom.: 2485 Cov.: 32 AF XY: 0.173 AC XY: 12846 AN XY: 74410

Gnomad4 AFR AF: 0.192

Gnomad4 AMR AF: 0.206

Gnomad4 ASJ AF: 0.221

Gnomad4 EAS AF: 0.0604

Gnomad4 SAS AF: 0.127

Gnomad4 FIN AF: 0.125

Gnomad4 NFE AF: 0.174

Gnomad4 OTH AF: 0.176

Alfa AF: 0.160 Hom.: 257

Bravo AF: 0.179

Asia WGS AF: 0.0970 AC: 335 AN: 3470

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

Oct 17, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	11
Dann	Benign	0.62

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: rs3790438; hg19: chr1-66085525; COSMIC: COSV60750180; COSMIC: COSV60750180;