1-65542217-C-T

Variant names:

• chr1-65542217-C-T
• rs1782763
• NM_002303.6:c.-20-23329C>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.-20-23329C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.656 in 151,872 control chromosomes in the GnomAD database, including 33,792 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 0.66 (33792 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• Publications: 10 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=-0.69).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002303.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	NM_002303.6	MANE Select	c.-20-23329C>T		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.-20-23329C>T		intron	N/A	NP_001003680.1
	LEPR	NM_001198687.2		c.-21+16399C>T		intron	N/A	NP_001185616.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.-20-23329C>T		intron	N/A	ENSP00000330393.7
	LEPR	ENST00000371059.7	TSL:1	c.-20-23329C>T		intron	N/A	ENSP00000360098.3
	LEPR	ENST00000344610.12	TSL:1	c.-21+16399C>T		intron	N/A	ENSP00000340884.8

Frequencies

GnomAD3 genomes AF: 0.656 AC: 99553 AN: 151754 Hom.: 33770 Cov.: 32

Gnomad AFR AF: 0.739

Gnomad AMI AF: 0.751

Gnomad AMR AF: 0.691

Gnomad ASJ AF: 0.722

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.556

Gnomad FIN AF: 0.515

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.663

Gnomad OTH AF: 0.668

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

GnomAD4 genome AF: 0.656 AC: 99621 AN: 151872 Hom.: 33792 Cov.: 32 AF XY: 0.646 AC XY: 47953 AN XY: 74256

African (AFR) AF: 0.738 AC: 30607 AN: 41450

American (AMR) AF: 0.691 AC: 10536 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.722 AC: 2504 AN: 3470

East Asian (EAS) AF: 0.115 AC: 594 AN: 5168

South Asian (SAS) AF: 0.557 AC: 2683 AN: 4816

European-Finnish (FIN) AF: 0.515 AC: 5395 AN: 10482

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.662 AC: 44993 AN: 67914

Other (OTH) AF: 0.661 AC: 1398 AN: 2114

Alfa AF: 0.693 Hom.: 8523

Bravo AF: 0.674

Asia WGS AF: 0.365 AC: 1267 AN: 3458

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	3.9
DANN	Benign	0.84
PhyloP100		-1.1
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: rs1782763; hg19: chr1-66007900;