1-65425500-T-A

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.-21+122T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 718,438 control chromosomes in the GnomAD database, including 214 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.027 (147 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (67 hom.)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.214

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]

LEPROT (HGNC:29477): (leptin receptor overlapping transcript) LEPROT is associated with the Golgi complex and endosomes and has a role in cell surface expression of growth hormone receptor (GHR; MIM 600946) and leptin receptor (OBR, or LEPR; MIM 601007), thereby altering receptor-mediated cell signaling (Couturier et al., 2007 [PubMed 18042720]; Touvier et al., 2009 [PubMed 19907080]).[supplied by OMIM, Jul 2010]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-65425500-T-A is Benign according to our data. Variant chr1-65425500-T-A is described in ClinVar as [Benign]. Clinvar id is 1225396.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPR	NM_002303.6	c.-21+122T>A		intron_variant		ENST00000349533.11
LEPROT	NM_017526.5	c.92+122T>A		intron_variant		ENST00000371065.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPR	ENST00000349533.11	c.-21+122T>A		intron_variant		1	NM_002303.6	P4
LEPROT	ENST00000371065.9	c.92+122T>A		intron_variant		1	NM_017526.5	P1

Frequencies

GnomAD3 genomes AF: 0.0266 AC: 4051 AN: 152178 Hom.: 143 Cov.: 32

Gnomad AFR AF: 0.0799

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0188

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00510

Gnomad OTH AF: 0.0234

GnomAD4 exome AF: 0.00769 AC: 4354 AN: 566142 Hom.: 67 AF XY: 0.00783 AC XY: 2316 AN XY: 295974

Gnomad4 AFR exome AF: 0.0790

Gnomad4 AMR exome AF: 0.00844

Gnomad4 ASJ exome AF: 0.0229

Gnomad4 EAS exome AF: 0.000142

Gnomad4 SAS exome AF: 0.0167

Gnomad4 FIN exome AF: 0.000708

Gnomad4 NFE exome AF: 0.00448

Gnomad4 OTH exome AF: 0.0147

GnomAD4 genome AF: 0.0268 AC: 4083 AN: 152296 Hom.: 147 Cov.: 32 AF XY: 0.0256 AC XY: 1907 AN XY: 74470

Gnomad4 AFR AF: 0.0804

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0186

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00510

Gnomad4 OTH AF: 0.0256

Alfa AF: 0.0201 Hom.: 14

Bravo AF: 0.0291

Asia WGS AF: 0.0330 AC: 115 AN: 3478

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

May 21, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	2.9
Dann	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs9436298; hg19: chr1-65891183;