chr1-65509592-C-T

Variant names:

• chr1-65509592-C-T
• rs7526141
• NM_002303.6:c.-20-55954C>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.-20-55954C>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 151,786 control chromosomes in the GnomAD database, including 10,178 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 (10178 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.58
• 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=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.-20-55954C>T		intron_variant	Intron 2 of 19	ENST00000349533.11	NP_002294.2
LEPR	NM_001003680.3	c.-20-55954C>T		intron_variant	Intron 2 of 19		NP_001003680.1
LEPR	NM_001003679.3	c.-20-55954C>T		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.-20-55954C>T		intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7
LEPR	ENST00000371059.7	c.-20-55954C>T		intron_variant	Intron 2 of 19	1		ENSP00000360098.3
LEPR	ENST00000371060.7	c.-20-55954C>T		intron_variant	Intron 2 of 19	1		ENSP00000360099.3

Frequencies

GnomAD3 genomes AF: 0.324 AC: 49174 AN: 151668 Hom.: 10181 Cov.: 32

Gnomad AFR AF: 0.0879

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.0220

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.440

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.464

Gnomad OTH AF: 0.361

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

GnomAD4 genome AF: 0.324 AC: 49174 AN: 151786 Hom.: 10178 Cov.: 32 AF XY: 0.320 AC XY: 23720 AN XY: 74152

African (AFR) AF: 0.0879 AC: 3637 AN: 41388

American (AMR) AF: 0.359 AC: 5476 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 1415 AN: 3470

East Asian (EAS) AF: 0.0224 AC: 116 AN: 5174

South Asian (SAS) AF: 0.244 AC: 1176 AN: 4820

European-Finnish (FIN) AF: 0.440 AC: 4602 AN: 10460

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.464 AC: 31521 AN: 67924

Other (OTH) AF: 0.358 AC: 753 AN: 2106

Alfa AF: 0.245 Hom.: 701

Bravo AF: 0.311

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.16
DANN	Benign	0.61
PhyloP100		-1.6
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: rs7526141; hg19: chr1-65975275;