NM_017526.5:c.*267G>T

Variant names:

• chr1-65432186-G-T
• rs7883
• NM_017526.5:c.*267G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017526.5(LEPROT):​c.*267G>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 0.00000104 in 958,932 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: LEPROT NM_017526.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.968
• Publications: 0 publications found

Genes affected

LEPROT (HGNC:29477): (leptin receptor overlapping transcript) LEPROT is associated with the Golgi complex and endosomes and has a role in cell surface expression of growth hormone receptor (GHR; MIM 600946) and leptin receptor (OBR, or LEPR; MIM 601007), thereby altering receptor-mediated cell signaling (Couturier et al., 2007 [PubMed 18042720]; Touvier et al., 2009 [PubMed 19907080]).[supplied by OMIM, Jul 2010]

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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017526.5. 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
	LEPROT	NM_017526.5	MANE Select	c.*267G>T		3_prime_UTR	Exon 4 of 4	NP_059996.1
	LEPR	NM_002303.6	MANE Select	c.-21+6808G>T		intron	N/A	NP_002294.2
	LEPROT	NM_001198681.2		c.*267G>T		3_prime_UTR	Exon 5 of 5	NP_001185610.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPROT	ENST00000371065.9	TSL:1 MANE Select	c.*267G>T		3_prime_UTR	Exon 4 of 4	ENSP00000360104.4
	LEPROT	ENST00000613538.1	TSL:1	c.*267G>T		3_prime_UTR	Exon 5 of 5	ENSP00000483521.1
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.-21+6808G>T		intron	N/A	ENSP00000330393.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000104 AC: 1 AN: 958932 Hom.: 0 Cov.: 30 AF XY: 0.00000221 AC XY: 1 AN XY: 452018

African (AFR) AF: 0.00 AC: 0 AN: 18876

American (AMR) AF: 0.00 AC: 0 AN: 5440

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9172

East Asian (EAS) AF: 0.00 AC: 0 AN: 9948

South Asian (SAS) AF: 0.0000312 AC: 1 AN: 32080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2202

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840018

Other (OTH) AF: 0.00 AC: 0 AN: 34672

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.013
DANN	Benign	0.54
PhyloP100		-0.97

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: rs7883; hg19: chr1-65897869;