NM_002303.6:c.-21+68336T>C

Variant names:

• chr1-65493714-T-C
• rs1327120
• NM_002303.6:c.-21+68336T>C

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+68336T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 151,846 control chromosomes in the GnomAD database, including 25,156 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 0.57 (25156 hom., cov: 31)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.50
• Publications: 5 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

ENSG00000237852 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.597 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.-21+68336T>C		intron_variant	Intron 2 of 19	ENST00000349533.11	NP_002294.2
LEPR	NM_001003680.3	c.-21+68336T>C		intron_variant	Intron 2 of 19		NP_001003680.1
LEPR	NM_001003679.3	c.-21+68336T>C		intron_variant	Intron 2 of 19		NP_001003679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.-21+68336T>C		intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7
LEPR	ENST00000371059.7	c.-21+68336T>C		intron_variant	Intron 2 of 19	1		ENSP00000360098.3
LEPR	ENST00000371060.7	c.-21+68336T>C		intron_variant	Intron 2 of 19	1		ENSP00000360099.3
ENSG00000237852	ENST00000429871.1	n.102-153T>C		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.567 AC: 86023 AN: 151728 Hom.: 25147 Cov.: 31

Gnomad AFR AF: 0.578

Gnomad AMI AF: 0.597

Gnomad AMR AF: 0.593

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.0791

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.717

Gnomad NFE AF: 0.602

Gnomad OTH AF: 0.584

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

GnomAD4 genome AF: 0.567 AC: 86071 AN: 151846 Hom.: 25156 Cov.: 31 AF XY: 0.558 AC XY: 41426 AN XY: 74194

African (AFR) AF: 0.578 AC: 23942 AN: 41414

American (AMR) AF: 0.593 AC: 9019 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.662 AC: 2296 AN: 3466

East Asian (EAS) AF: 0.0794 AC: 411 AN: 5174

South Asian (SAS) AF: 0.535 AC: 2577 AN: 4820

European-Finnish (FIN) AF: 0.472 AC: 4979 AN: 10554

Middle Eastern (MID) AF: 0.709 AC: 207 AN: 292

European-Non Finnish (NFE) AF: 0.602 AC: 40875 AN: 67898

Other (OTH) AF: 0.581 AC: 1222 AN: 2102

Alfa AF: 0.593 Hom.: 5056

Bravo AF: 0.576

Asia WGS AF: 0.333 AC: 1161 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.094
DANN	Benign	0.43
PhyloP100		-2.5
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: rs1327120; hg19: chr1-65959397;