chr1-65527665-G-A

Variant names:

• chr1-65527665-G-A
• rs1782754
• NM_002303.6:c.-20-37881G>A

Variant summary

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

The NM_002303.6(LEPR):​c.-20-37881G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.706 in 152,032 control chromosomes in the GnomAD database, including 38,788 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 0.71 (38788 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.317
• Publications: 12 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.802 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	NM_002303.6	MANE Select	c.-20-37881G>A		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.-20-37881G>A		intron	N/A	NP_001003680.1	P48357-3
	LEPR	NM_001198687.2		c.-21+1847G>A		intron	N/A	NP_001185616.1	P48357-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.-20-37881G>A		intron	N/A	ENSP00000330393.7	P48357-1
	LEPR	ENST00000371059.7	TSL:1	c.-20-37881G>A		intron	N/A	ENSP00000360098.3	P48357-3
	LEPR	ENST00000344610.12	TSL:1	c.-21+1847G>A		intron	N/A	ENSP00000340884.8	P48357-4

Frequencies

GnomAD3 genomes AF: 0.706 AC: 107178 AN: 151914 Hom.: 38759 Cov.: 32

Gnomad AFR AF: 0.728

Gnomad AMI AF: 0.802

Gnomad AMR AF: 0.728

Gnomad ASJ AF: 0.840

Gnomad EAS AF: 0.171

Gnomad SAS AF: 0.824

Gnomad FIN AF: 0.598

Gnomad MID AF: 0.885

Gnomad NFE AF: 0.726

Gnomad OTH AF: 0.739

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

GnomAD4 genome AF: 0.706 AC: 107260 AN: 152032 Hom.: 38788 Cov.: 32 AF XY: 0.700 AC XY: 52040 AN XY: 74294

African (AFR) AF: 0.728 AC: 30199 AN: 41472

American (AMR) AF: 0.728 AC: 11122 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.840 AC: 2914 AN: 3468

East Asian (EAS) AF: 0.171 AC: 886 AN: 5170

South Asian (SAS) AF: 0.824 AC: 3974 AN: 4824

European-Finnish (FIN) AF: 0.598 AC: 6296 AN: 10536

Middle Eastern (MID) AF: 0.884 AC: 258 AN: 292

European-Non Finnish (NFE) AF: 0.726 AC: 49330 AN: 67968

Other (OTH) AF: 0.735 AC: 1553 AN: 2112

Alfa AF: 0.718 Hom.: 66945

Bravo AF: 0.711

Asia WGS AF: 0.555 AC: 1931 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.47
DANN	Benign	0.67
PhyloP100		-0.32
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: rs1782754; hg19: chr1-65993348; COSMIC: COSV60763324;