rs9436740

Variant names:

• chr1-65426218-A-T
• rs9436740
• NM_002303.6:c.-21+840A>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+840A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.324 in 145,502 control chromosomes in the GnomAD database, including 7,875 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 0.32 (7875 hom., cov: 31)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.760
• Publications: 11 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]

LEPROT (HGNC:29477): (leptin receptor overlapping transcript) LEPROT is associated with the Golgi complex and endosomes and has a role in cell surface expression of growth hormone receptor (GHR; MIM 600946) and leptin receptor (OBR, or LEPR; MIM 601007), thereby altering receptor-mediated cell signaling (Couturier et al., 2007 [PubMed 18042720]; Touvier et al., 2009 [PubMed 19907080]).[supplied by OMIM, Jul 2010]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.463 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+840A>T		intron	N/A	NP_002294.2
	LEPROT	NM_017526.5	MANE Select	c.92+840A>T		intron	N/A	NP_059996.1	O15243
	LEPR	NM_001003680.3		c.-21+840A>T		intron	N/A	NP_001003680.1	P48357-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.-21+840A>T		intron	N/A	ENSP00000330393.7	P48357-1
	LEPROT	ENST00000371065.9	TSL:1 MANE Select	c.92+840A>T		intron	N/A	ENSP00000360104.4	O15243
	LEPR	ENST00000371059.7	TSL:1	c.-21+840A>T		intron	N/A	ENSP00000360098.3	P48357-3

Frequencies

GnomAD3 genomes AF: 0.323 AC: 47010 AN: 145382 Hom.: 7859 Cov.: 31

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.460

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.347

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.298

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

GnomAD4 genome AF: 0.324 AC: 47093 AN: 145502 Hom.: 7875 Cov.: 31 AF XY: 0.321 AC XY: 22872 AN XY: 71186

African (AFR) AF: 0.469 AC: 16901 AN: 36042

American (AMR) AF: 0.260 AC: 3843 AN: 14804

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 1141 AN: 3344

East Asian (EAS) AF: 0.170 AC: 870 AN: 5114

South Asian (SAS) AF: 0.271 AC: 1299 AN: 4792

European-Finnish (FIN) AF: 0.285 AC: 3012 AN: 10560

Middle Eastern (MID) AF: 0.343 AC: 96 AN: 280

European-Non Finnish (NFE) AF: 0.280 AC: 18906 AN: 67632

Other (OTH) AF: 0.299 AC: 606 AN: 2024

Alfa AF: 0.327 Hom.: 880

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.62
DANN	Benign	0.83
PhyloP100		-0.76
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: rs9436740; hg19: chr1-65891901;