1-65570345-A-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.41-128A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 817,680 control chromosomes in the GnomAD database, including 20,383 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.23 (4231 hom., cov: 33)
  • Exomes 𝑓: 0.21 (16152 hom.)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.298

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=-0.89).
• BP6: Variant 1-65570345-A-G is Benign according to our data. Variant chr1-65570345-A-G is described in ClinVar as [Benign]. Clinvar id is 1244528.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPR	NM_002303.6	c.41-128A>G		intron_variant		ENST00000349533.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPR	ENST00000349533.11	c.41-128A>G		intron_variant		1	NM_002303.6	P4

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34387 AN: 152048 Hom.: 4224 Cov.: 33

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.0642

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.224

GnomAD4 exome AF: 0.215 AC: 142762 AN: 665514 Hom.: 16152 AF XY: 0.218 AC XY: 74963 AN XY: 343332

Gnomad4 AFR exome AF: 0.269

Gnomad4 AMR exome AF: 0.124

Gnomad4 ASJ exome AF: 0.271

Gnomad4 EAS exome AF: 0.0726

Gnomad4 SAS exome AF: 0.294

Gnomad4 FIN exome AF: 0.260

Gnomad4 NFE exome AF: 0.213

Gnomad4 OTH exome AF: 0.216

GnomAD4 genome AF: 0.226 AC: 34418 AN: 152166 Hom.: 4231 Cov.: 33 AF XY: 0.226 AC XY: 16829 AN XY: 74376

Gnomad4 AFR AF: 0.269

Gnomad4 AMR AF: 0.151

Gnomad4 ASJ AF: 0.291

Gnomad4 EAS AF: 0.0640

Gnomad4 SAS AF: 0.289

Gnomad4 FIN AF: 0.257

Gnomad4 NFE AF: 0.218

Gnomad4 OTH AF: 0.226

Alfa AF: 0.218 Hom.: 656

Bravo AF: 0.216

Asia WGS AF: 0.235 AC: 815 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

Aug 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	3.0
Dann	Benign	0.73

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: rs3790431; hg19: chr1-66036028;