1-65533107-C-T

Variant names:

• chr1-65533107-C-T
• rs1171271
• NM_002303.6:c.-20-32439C>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.-20-32439C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.727 in 151,984 control chromosomes in the GnomAD database, including 41,294 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 0.73 (41294 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.698
• Publications: 8 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=-1.03).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.802 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.-20-32439C>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.-20-32439C>T		intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.727 AC: 110467 AN: 151866 Hom.: 41263 Cov.: 32

Gnomad AFR AF: 0.801

Gnomad AMI AF: 0.801

Gnomad AMR AF: 0.738

Gnomad ASJ AF: 0.844

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.824

Gnomad FIN AF: 0.599

Gnomad MID AF: 0.902

Gnomad NFE AF: 0.727

Gnomad OTH AF: 0.748

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

GnomAD4 genome AF: 0.727 AC: 110551 AN: 151984 Hom.: 41294 Cov.: 32 AF XY: 0.721 AC XY: 53560 AN XY: 74268

African (AFR) AF: 0.801 AC: 33239 AN: 41478

American (AMR) AF: 0.738 AC: 11264 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.844 AC: 2927 AN: 3470

East Asian (EAS) AF: 0.173 AC: 894 AN: 5162

South Asian (SAS) AF: 0.824 AC: 3962 AN: 4810

European-Finnish (FIN) AF: 0.599 AC: 6309 AN: 10534

Middle Eastern (MID) AF: 0.901 AC: 265 AN: 294

European-Non Finnish (NFE) AF: 0.727 AC: 49391 AN: 67942

Other (OTH) AF: 0.744 AC: 1574 AN: 2116

Alfa AF: 0.740 Hom.: 10685

Bravo AF: 0.736

Asia WGS AF: 0.563 AC: 1953 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.14
PhyloP100		-0.70
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: rs1171271; hg19: chr1-65998790;