rs9436743

Variant names:

• chr1-65435436-T-C
• rs9436743
• NM_017526.5:c.*3517T>C

Variant summary

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

The NM_017526.5(LEPROT):​c.*3517T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.691 in 628,538 control chromosomes in the GnomAD database, including 151,300 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 0.69 (36586 hom., cov: 23)
  • Exomes 𝑓: 0.69 (114714 hom.)
• Consequence: LEPROT NM_017526.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.85
• Publications: 3 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=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.791 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPROT	NM_017526.5	c.*3517T>C		3_prime_UTR_variant	Exon 4 of 4	ENST00000371065.9	NP_059996.1
LEPR	NM_002303.6	c.-21+10058T>C		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.*3517T>C		3_prime_UTR_variant	Exon 4 of 4	1	NM_017526.5	ENSP00000360104.4
LEPR	ENST00000349533.11	c.-21+10058T>C		intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.692 AC: 102607 AN: 148358 Hom.: 36574 Cov.: 23

Gnomad AFR AF: 0.799

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.667

Gnomad ASJ AF: 0.780

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.720

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.815

Gnomad NFE AF: 0.689

Gnomad OTH AF: 0.688

GnomAD4 exome AF: 0.691 AC: 331500 AN: 480076 Hom.: 114714 Cov.: 6 AF XY: 0.692 AC XY: 156563 AN XY: 226308

African (AFR) AF: 0.807 AC: 7202 AN: 8928

American (AMR) AF: 0.689 AC: 390 AN: 566

Ashkenazi Jewish (ASJ) AF: 0.773 AC: 2273 AN: 2940

East Asian (EAS) AF: 0.166 AC: 328 AN: 1976

South Asian (SAS) AF: 0.725 AC: 6624 AN: 9142

European-Finnish (FIN) AF: 0.527 AC: 77 AN: 146

Middle Eastern (MID) AF: 0.808 AC: 753 AN: 932

European-Non Finnish (NFE) AF: 0.689 AC: 303273 AN: 440004

Other (OTH) AF: 0.685 AC: 10580 AN: 15442

GnomAD4 genome AF: 0.692 AC: 102663 AN: 148462 Hom.: 36586 Cov.: 23 AF XY: 0.681 AC XY: 49228 AN XY: 72272

African (AFR) AF: 0.799 AC: 31849 AN: 39882

American (AMR) AF: 0.666 AC: 9947 AN: 14942

Ashkenazi Jewish (ASJ) AF: 0.780 AC: 2693 AN: 3452

East Asian (EAS) AF: 0.170 AC: 866 AN: 5092

South Asian (SAS) AF: 0.720 AC: 3359 AN: 4666

European-Finnish (FIN) AF: 0.531 AC: 5233 AN: 9862

Middle Eastern (MID) AF: 0.812 AC: 237 AN: 292

European-Non Finnish (NFE) AF: 0.689 AC: 46362 AN: 67330

Other (OTH) AF: 0.687 AC: 1403 AN: 2042

Alfa AF: 0.696 Hom.: 4577

Bravo AF: 0.704

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.92
DANN	Benign	0.69
PhyloP100		-1.9
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: rs9436743; hg19: chr1-65901119;