rs10789184

Variant names:

• chr1-65571279-G-A
• rs10789184
• NM_002303.6:c.370+477G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-65571279-G-A
• chr1-65571279-G-C
• chr1-65571279-G-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.370+477G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 151,800 control chromosomes in the GnomAD database, including 6,218 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 0.26 (6218 hom., cov: 31)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.365
• Publications: 7 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.79 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.370+477G>A		intron_variant	Intron 4 of 19	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.370+477G>A		intron_variant	Intron 4 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39256 AN: 151682 Hom.: 6214 Cov.: 31

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.811

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.0987

Gnomad NFE AF: 0.268

Gnomad OTH AF: 0.246

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

GnomAD4 genome AF: 0.259 AC: 39270 AN: 151800 Hom.: 6218 Cov.: 31 AF XY: 0.264 AC XY: 19548 AN XY: 74162

African (AFR) AF: 0.167 AC: 6928 AN: 41368

American (AMR) AF: 0.260 AC: 3963 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 502 AN: 3468

East Asian (EAS) AF: 0.811 AC: 4190 AN: 5168

South Asian (SAS) AF: 0.174 AC: 835 AN: 4806

European-Finnish (FIN) AF: 0.372 AC: 3900 AN: 10488

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.268 AC: 18230 AN: 67924

Other (OTH) AF: 0.250 AC: 526 AN: 2106

Alfa AF: 0.225 Hom.: 1196

Bravo AF: 0.250

Asia WGS AF: 0.414 AC: 1435 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.2
DANN	Benign	0.45
PhyloP100		0.36
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: rs10789184; hg19: chr1-66036962;