rs1887285

Variant names:

• chr1-65432064-A-G
• rs1887285
• NM_017526.5:c.*145A>G

Variant summary

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

The NM_017526.5(LEPROT):​c.*145A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0896 in 1,350,772 control chromosomes in the GnomAD database, including 5,864 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 0.096 (781 hom., cov: 33)
  • Exomes 𝑓: 0.089 (5083 hom.)
• Consequence: LEPROT NM_017526.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.04
• Publications: 28 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPROT	NM_017526.5	c.*145A>G		3_prime_UTR_variant	Exon 4 of 4	ENST00000371065.9	NP_059996.1
LEPR	NM_002303.6	c.-21+6686A>G		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.*145A>G		3_prime_UTR_variant	Exon 4 of 4	1	NM_017526.5	ENSP00000360104.4
LEPR	ENST00000349533.11	c.-21+6686A>G		intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.0956 AC: 14538 AN: 152000 Hom.: 782 Cov.: 33

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.0809

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0763

Gnomad FIN AF: 0.0771

Gnomad MID AF: 0.0924

Gnomad NFE AF: 0.0917

Gnomad OTH AF: 0.0899

GnomAD4 exome AF: 0.0888 AC: 106479 AN: 1198658 Hom.: 5083 Cov.: 27 AF XY: 0.0887 AC XY: 51356 AN XY: 578692

African (AFR) AF: 0.129 AC: 3247 AN: 25200

American (AMR) AF: 0.0629 AC: 855 AN: 13598

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 2083 AN: 16760

East Asian (EAS) AF: 0.000265 AC: 8 AN: 30242

South Asian (SAS) AF: 0.0771 AC: 3677 AN: 47696

European-Finnish (FIN) AF: 0.0719 AC: 2109 AN: 29352

Middle Eastern (MID) AF: 0.144 AC: 470 AN: 3268

European-Non Finnish (NFE) AF: 0.0913 AC: 89827 AN: 983736

Other (OTH) AF: 0.0861 AC: 4203 AN: 48806

GnomAD4 genome AF: 0.0956 AC: 14544 AN: 152114 Hom.: 781 Cov.: 33 AF XY: 0.0949 AC XY: 7059 AN XY: 74358

African (AFR) AF: 0.121 AC: 5026 AN: 41516

American (AMR) AF: 0.0808 AC: 1236 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 470 AN: 3456

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5184

South Asian (SAS) AF: 0.0759 AC: 360 AN: 4742

European-Finnish (FIN) AF: 0.0771 AC: 818 AN: 10608

Middle Eastern (MID) AF: 0.0993 AC: 29 AN: 292

European-Non Finnish (NFE) AF: 0.0917 AC: 6234 AN: 68000

Other (OTH) AF: 0.0890 AC: 188 AN: 2112

Alfa AF: 0.0937 Hom.: 1733

Bravo AF: 0.0958

Asia WGS AF: 0.0440 AC: 152 AN: 3440

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.050
DANN	Benign	0.71
PhyloP100		-2.0
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: rs1887285; hg19: chr1-65897747;