NM_002303.6:c.370+291T>A

Variant names:

• chr1-65571093-T-A
• rs3790429
• NM_002303.6:c.370+291T>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.370+291T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 152,216 control chromosomes in the GnomAD database, including 1,698 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 0.14 (1698 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0110
• Publications: 9 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.370+291T>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+291T>A		intron_variant	Intron 4 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21487 AN: 152098 Hom.: 1697 Cov.: 32

Gnomad AFR AF: 0.0916

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.0400

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.164

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

GnomAD4 genome AF: 0.141 AC: 21503 AN: 152216 Hom.: 1698 Cov.: 32 AF XY: 0.139 AC XY: 10379 AN XY: 74408

African (AFR) AF: 0.0918 AC: 3815 AN: 41558

American (AMR) AF: 0.222 AC: 3393 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 651 AN: 3472

East Asian (EAS) AF: 0.0403 AC: 209 AN: 5184

South Asian (SAS) AF: 0.120 AC: 579 AN: 4828

European-Finnish (FIN) AF: 0.112 AC: 1182 AN: 10564

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.164 AC: 11127 AN: 68006

Other (OTH) AF: 0.162 AC: 343 AN: 2116

Alfa AF: 0.145 Hom.: 212

Bravo AF: 0.147

Asia WGS AF: 0.0880 AC: 304 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.1
DANN	Benign	0.72
PhyloP100		0.011
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: rs3790429; hg19: chr1-66036776; COSMIC: COSV60749909;