1-65620511-A-T

Variant names:

• chr1-65620511-A-T
• rs10889569
• NM_002303.6:c.2491+488A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002303.6(LEPR):​c.2491+488A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 151,928 control chromosomes in the GnomAD database, including 17,194 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.46 (17194 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0220
• Publications: 14 publications found

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]

LEPR Gene-Disease associations (from GenCC):

• obesity due to leptin receptor gene deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.848 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.2491+488A>T		intron_variant	Intron 17 of 19	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.2491+488A>T		intron_variant	Intron 17 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.463 AC: 70273 AN: 151810 Hom.: 17157 Cov.: 32

Gnomad AFR AF: 0.549

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.375

Gnomad EAS AF: 0.870

Gnomad SAS AF: 0.464

Gnomad FIN AF: 0.490

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.436

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.463 AC: 70366 AN: 151928 Hom.: 17194 Cov.: 32 AF XY: 0.470 AC XY: 34914 AN XY: 74234

African (AFR) AF: 0.549 AC: 22752 AN: 41408

American (AMR) AF: 0.485 AC: 7391 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 1302 AN: 3470

East Asian (EAS) AF: 0.869 AC: 4483 AN: 5156

South Asian (SAS) AF: 0.463 AC: 2234 AN: 4830

European-Finnish (FIN) AF: 0.490 AC: 5163 AN: 10544

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.378 AC: 25698 AN: 67960

Other (OTH) AF: 0.443 AC: 934 AN: 2110

Alfa AF: 0.411 Hom.: 1628

Bravo AF: 0.466

Asia WGS AF: 0.627 AC: 2175 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.0
DANN	Benign	0.43
PhyloP100		0.022
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10889569; hg19: chr1-66086194; COSMIC: COSV60750197;