chr1-65565531-A-T

Variant names:

• chr1-65565531-A-T
• rs116571599
• NM_002303.6:c.-20-15A>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_002303.6(LEPR):​c.-20-15A>T variant causes a 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 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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.-20-15A>T		intron_variant	Intron 2 of 19	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.-20-15A>T		intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7

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

GnomAD2 exomes AF: 0.00411 AC: 1031 AN: 250884 AF XY: 0.00438

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 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 AC: 40 AN: 33462

Gnomad4 AMR exome AF: 0.00208 AC: 93 AN: 44712

Gnomad4 ASJ exome AF: 0.00184 AC: 48 AN: 26110

Gnomad4 EAS exome AF: 0.0000253 AC: 1 AN: 39600

Gnomad4 SAS exome AF: 0.00564 AC: 486 AN: 86212

Gnomad4 FIN exome AF: 0.00187 AC: 100 AN: 53382

Gnomad4 NFE exome AF: 0.00778 AC: 8646 AN: 1111708

Gnomad4 Remaining exome AF: 0.00572 AC: 345 AN: 60366

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 AC: 0.00134816 AN: 0.00134816

Gnomad4 AMR AF: 0.00281 AC: 0.00281193 AN: 0.00281193

Gnomad4 ASJ AF: 0.00115 AC: 0.00115207 AN: 0.00115207

Gnomad4 EAS AF: 0.000193 AC: 0.000192976 AN: 0.000192976

Gnomad4 SAS AF: 0.00519 AC: 0.00518888 AN: 0.00518888

Gnomad4 FIN AF: 0.00160 AC: 0.00160377 AN: 0.00160377

Gnomad4 NFE AF: 0.00684 AC: 0.00683884 AN: 0.00683884

Gnomad4 OTH AF: 0.00427 AC: 0.0042654 AN: 0.0042654

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Obesity due to leptin receptor gene deficiency Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	13
DANN	Benign	0.68
Mutation Taster		=100/0	polymorphism

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;