1-65565531-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_002303.6(LEPR):c.-20-15A>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00649 in 1,613,526 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0046 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (33 hom.)
• Consequence: LEPR NM_002303.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.439

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00456 (694/152212) while in subpopulation NFE AF= 0.00684 (465/67994). AF 95% confidence interval is 0.00632. There are 10 homozygotes in gnomad4. There are 285 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPR	NM_002303.6	c.-20-15A>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000349533.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPR	ENST00000349533.11	c.-20-15A>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002303.6	P4

Frequencies

GnomAD3 genomes AF: 0.00456 AC: 694 AN: 152094 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00684

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00411 AC: 1031 AN: 250884 Hom.: 7 AF XY: 0.00438 AC XY: 594 AN XY: 135630

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00533

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.00611

Gnomad OTH exome AF: 0.00409

GnomAD4 exome AF: 0.00670 AC: 9785 AN: 1461314 Hom.: 33 Cov.: 31 AF XY: 0.00660 AC XY: 4801 AN XY: 726950

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.00184

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00564

Gnomad4 FIN exome AF: 0.00187

Gnomad4 NFE exome AF: 0.00778

Gnomad4 OTH exome AF: 0.00572

GnomAD4 genome AF: 0.00456 AC: 694 AN: 152212 Hom.: 10 Cov.: 32 AF XY: 0.00383 AC XY: 285 AN XY: 74432

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00519

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00684

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00270 Hom.: 1

Bravo AF: 0.00466

Asia WGS AF: 0.00173 AC: 6 AN: 3474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Monogenic Non-Syndromic Obesity Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Obesity due to leptin receptor gene deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	13
Dann	Benign	0.68

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: rs116571599; hg19: chr1-66031214;