NM_017526.5:c.*267G>A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017526.5(LEPROT):​c.*267G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0587 in 1,110,814 control chromosomes in the GnomAD database, including 4,451 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 0.13 (2371 hom., cov: 32)
  • Exomes 𝑓: 0.048 (2080 hom.)
• Consequence: LEPROT NM_017526.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.968
• Publications: 11 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPROT	NM_017526.5	c.*267G>A		3_prime_UTR_variant	Exon 4 of 4	ENST00000371065.9	NP_059996.1
LEPR	NM_002303.6	c.-21+6808G>A		intron_variant	Intron 2 of 19	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPROT	ENST00000371065.9	c.*267G>A		3_prime_UTR_variant	Exon 4 of 4	1	NM_017526.5	ENSP00000360104.4
LEPR	ENST00000349533.11	c.-21+6808G>A		intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19508 AN: 151922 Hom.: 2365 Cov.: 32

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0621

Gnomad ASJ AF: 0.0631

Gnomad EAS AF: 0.0266

Gnomad SAS AF: 0.0968

Gnomad FIN AF: 0.0705

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0502

Gnomad OTH AF: 0.115

GnomAD4 exome AF: 0.0476 AC: 45652 AN: 958774 Hom.: 2080 Cov.: 30 AF XY: 0.0478 AC XY: 21600 AN XY: 451950

African (AFR) AF: 0.339 AC: 6395 AN: 18860

American (AMR) AF: 0.0565 AC: 307 AN: 5436

Ashkenazi Jewish (ASJ) AF: 0.0613 AC: 562 AN: 9166

East Asian (EAS) AF: 0.0317 AC: 315 AN: 9946

South Asian (SAS) AF: 0.0875 AC: 2804 AN: 32050

European-Finnish (FIN) AF: 0.0674 AC: 439 AN: 6518

Middle Eastern (MID) AF: 0.0858 AC: 189 AN: 2202

European-Non Finnish (NFE) AF: 0.0388 AC: 32552 AN: 839936

Other (OTH) AF: 0.0603 AC: 2089 AN: 34660

GnomAD4 genome AF: 0.129 AC: 19541 AN: 152040 Hom.: 2371 Cov.: 32 AF XY: 0.127 AC XY: 9447 AN XY: 74328

African (AFR) AF: 0.321 AC: 13313 AN: 41426

American (AMR) AF: 0.0618 AC: 943 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0631 AC: 219 AN: 3470

East Asian (EAS) AF: 0.0265 AC: 137 AN: 5174

South Asian (SAS) AF: 0.0959 AC: 462 AN: 4820

European-Finnish (FIN) AF: 0.0705 AC: 745 AN: 10570

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.0502 AC: 3415 AN: 68012

Other (OTH) AF: 0.115 AC: 241 AN: 2104

Alfa AF: 0.0850 Hom.: 527

Bravo AF: 0.134

Asia WGS AF: 0.0850 AC: 294 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.024
DANN	Benign	0.55
PhyloP100		-0.97
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: rs7883; hg19: chr1-65897869; COSMIC: COSV105239700; COSMIC: COSV105239700;