chr1-65469811-G-A

Variant names:

• chr1-65469811-G-A
• rs6588147
• NM_002303.6:c.-21+44433G>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.-21+44433G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.688 in 152,118 control chromosomes in the GnomAD database, including 37,399 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 0.69 (37399 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0630
• Publications: 33 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: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.83 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.-21+44433G>A		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.-21+44433G>A		intron	N/A	NP_001003680.1
	LEPR	NM_001003679.3		c.-21+44433G>A		intron	N/A	NP_001003679.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.-21+44433G>A		intron	N/A	ENSP00000330393.7
	LEPR	ENST00000371059.7	TSL:1	c.-21+44433G>A		intron	N/A	ENSP00000360098.3
	LEPR	ENST00000371060.7	TSL:1	c.-21+44433G>A		intron	N/A	ENSP00000360099.3

Frequencies

GnomAD3 genomes AF: 0.687 AC: 104488 AN: 152000 Hom.: 37355 Cov.: 32

Gnomad AFR AF: 0.837

Gnomad AMI AF: 0.649

Gnomad AMR AF: 0.654

Gnomad ASJ AF: 0.784

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.699

Gnomad FIN AF: 0.532

Gnomad MID AF: 0.804

Gnomad NFE AF: 0.664

Gnomad OTH AF: 0.694

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

GnomAD4 genome AF: 0.688 AC: 104584 AN: 152118 Hom.: 37399 Cov.: 32 AF XY: 0.678 AC XY: 50381 AN XY: 74346

African (AFR) AF: 0.837 AC: 34768 AN: 41532

American (AMR) AF: 0.652 AC: 9971 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 2722 AN: 3472

East Asian (EAS) AF: 0.143 AC: 739 AN: 5170

South Asian (SAS) AF: 0.699 AC: 3371 AN: 4824

European-Finnish (FIN) AF: 0.532 AC: 5613 AN: 10556

Middle Eastern (MID) AF: 0.803 AC: 236 AN: 294

European-Non Finnish (NFE) AF: 0.664 AC: 45112 AN: 67970

Other (OTH) AF: 0.693 AC: 1463 AN: 2110

Alfa AF: 0.686 Hom.: 60372

Bravo AF: 0.699

Asia WGS AF: 0.489 AC: 1703 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.3
DANN	Benign	0.35
PhyloP100		0.063
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: rs6588147; hg19: chr1-65935494;