1-65640261-C-T

Variant names:

• chr1-65640261-C-T
• rs1892534
• NM_002303.6:c.*3246C>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.*3246C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.442 in 151,948 control chromosomes in the GnomAD database, including 15,547 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 (15547 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: LEPR NM_002303.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.57
• Publications: 60 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.848 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002303.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	NM_002303.6	MANE Select	c.*3246C>T		3_prime_UTR	Exon 20 of 20	NP_002294.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.*3246C>T		3_prime_UTR	Exon 20 of 20	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.441 AC: 67012 AN: 151830 Hom.: 15509 Cov.: 32

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.479

Gnomad ASJ AF: 0.375

Gnomad EAS AF: 0.870

Gnomad SAS AF: 0.465

Gnomad FIN AF: 0.508

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.419

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.442 AC: 67111 AN: 151948 Hom.: 15547 Cov.: 32 AF XY: 0.450 AC XY: 33439 AN XY: 74264

African (AFR) AF: 0.454 AC: 18822 AN: 41440

American (AMR) AF: 0.479 AC: 7314 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 1298 AN: 3462

East Asian (EAS) AF: 0.869 AC: 4491 AN: 5166

South Asian (SAS) AF: 0.463 AC: 2233 AN: 4818

European-Finnish (FIN) AF: 0.508 AC: 5357 AN: 10548

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.387 AC: 26270 AN: 67940

Other (OTH) AF: 0.426 AC: 899 AN: 2108

Alfa AF: 0.404 Hom.: 60961

Bravo AF: 0.440

Asia WGS AF: 0.624 AC: 2165 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.27
DANN	Benign	0.45
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: rs1892534; hg19: chr1-66105944;