1-65624099-C-T

Variant names:

• chr1-65624099-C-T
• rs6700896
• NM_002303.6:c.2673+1118C>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.2673+1118C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.441 in 151,880 control chromosomes in the GnomAD database, including 15,443 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 0.44 (15443 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08
• Publications: 43 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.848 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.2673+1118C>T		intron_variant	Intron 19 of 19	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.2673+1118C>T		intron_variant	Intron 19 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66837 AN: 151762 Hom.: 15411 Cov.: 32

Gnomad AFR AF: 0.449

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.480

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.870

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.494

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.388

Gnomad OTH AF: 0.418

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

GnomAD4 genome AF: 0.441 AC: 66933 AN: 151880 Hom.: 15443 Cov.: 32 AF XY: 0.449 AC XY: 33335 AN XY: 74220

African (AFR) AF: 0.450 AC: 18642 AN: 41412

American (AMR) AF: 0.481 AC: 7333 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 1354 AN: 3468

East Asian (EAS) AF: 0.869 AC: 4502 AN: 5180

South Asian (SAS) AF: 0.465 AC: 2240 AN: 4814

European-Finnish (FIN) AF: 0.494 AC: 5202 AN: 10530

Middle Eastern (MID) AF: 0.377 AC: 110 AN: 292

European-Non Finnish (NFE) AF: 0.388 AC: 26338 AN: 67908

Other (OTH) AF: 0.425 AC: 897 AN: 2112

Alfa AF: 0.411 Hom.: 47224

Bravo AF: 0.440

Asia WGS AF: 0.623 AC: 2164 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.072
DANN	Benign	0.20
PhyloP100		-1.1
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: rs6700896; hg19: chr1-66089782; COSMIC: COSV60750272; COSMIC: COSV60750272;