rs7531110

Variant names:

• chr1-65471382-G-T
• rs7531110
• NM_002303.6:c.-21+46004G>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.-21+46004G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.522 in 152,014 control chromosomes in the GnomAD database, including 21,600 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 0.52 (21600 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.268
• Publications: 6 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.592 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.-21+46004G>T		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.-21+46004G>T		intron	N/A	NP_001003680.1
	LEPR	NM_001003679.3		c.-21+46004G>T		intron	N/A	NP_001003679.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.-21+46004G>T		intron	N/A	ENSP00000330393.7
	LEPR	ENST00000371059.7	TSL:1	c.-21+46004G>T		intron	N/A	ENSP00000360098.3
	LEPR	ENST00000371060.7	TSL:1	c.-21+46004G>T		intron	N/A	ENSP00000360099.3

Frequencies

GnomAD3 genomes AF: 0.522 AC: 79352 AN: 151896 Hom.: 21598 Cov.: 32

Gnomad AFR AF: 0.429

Gnomad AMI AF: 0.593

Gnomad AMR AF: 0.570

Gnomad ASJ AF: 0.648

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.470

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.597

Gnomad OTH AF: 0.546

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

GnomAD4 genome AF: 0.522 AC: 79368 AN: 152014 Hom.: 21600 Cov.: 32 AF XY: 0.515 AC XY: 38290 AN XY: 74308

African (AFR) AF: 0.429 AC: 17776 AN: 41438

American (AMR) AF: 0.569 AC: 8697 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.648 AC: 2250 AN: 3470

East Asian (EAS) AF: 0.119 AC: 614 AN: 5178

South Asian (SAS) AF: 0.537 AC: 2585 AN: 4810

European-Finnish (FIN) AF: 0.470 AC: 4958 AN: 10548

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.597 AC: 40595 AN: 67972

Other (OTH) AF: 0.545 AC: 1153 AN: 2116

Alfa AF: 0.571 Hom.: 5514

Bravo AF: 0.526

Asia WGS AF: 0.337 AC: 1178 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.86
DANN	Benign	0.49
PhyloP100		-0.27
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: rs7531110; hg19: chr1-65937065;