1-65428659-C-T

Variant names:

• chr1-65428659-C-T
• rs3790433
• NM_002303.6:c.-21+3281C>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+3281C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 151,794 control chromosomes in the GnomAD database, including 14,616 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 0.39 (14616 hom., cov: 31)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.255
• Publications: 31 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.703 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+3281C>T		intron	N/A	NP_002294.2
	LEPROT	NM_017526.5	MANE Select	c.93-1203C>T		intron	N/A	NP_059996.1	O15243
	LEPR	NM_001003680.3		c.-21+3281C>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+3281C>T		intron	N/A	ENSP00000330393.7	P48357-1
	LEPROT	ENST00000371065.9	TSL:1 MANE Select	c.93-1203C>T		intron	N/A	ENSP00000360104.4	O15243
	LEPR	ENST00000371059.7	TSL:1	c.-21+3281C>T		intron	N/A	ENSP00000360098.3	P48357-3

Frequencies

GnomAD3 genomes AF: 0.389 AC: 59016 AN: 151676 Hom.: 14590 Cov.: 31

Gnomad AFR AF: 0.710

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.308

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.262

Gnomad OTH AF: 0.357

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

GnomAD4 genome AF: 0.389 AC: 59082 AN: 151794 Hom.: 14616 Cov.: 31 AF XY: 0.386 AC XY: 28613 AN XY: 74158

African (AFR) AF: 0.710 AC: 29383 AN: 41400

American (AMR) AF: 0.318 AC: 4857 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 1067 AN: 3466

East Asian (EAS) AF: 0.143 AC: 738 AN: 5152

South Asian (SAS) AF: 0.389 AC: 1869 AN: 4802

European-Finnish (FIN) AF: 0.215 AC: 2254 AN: 10476

Middle Eastern (MID) AF: 0.435 AC: 127 AN: 292

European-Non Finnish (NFE) AF: 0.262 AC: 17788 AN: 67940

Other (OTH) AF: 0.358 AC: 751 AN: 2100

Alfa AF: 0.287 Hom.: 11526

Bravo AF: 0.406

Asia WGS AF: 0.301 AC: 1051 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.1
DANN	Benign	0.23
PhyloP100		-0.26
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: rs3790433; hg19: chr1-65894342;