NM_017526.5:c.*349G>A

Variant names:

• chr1-65432268-G-A
• rs7602
• NM_017526.5:c.*349G>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.*349G>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 0.226 in 1,000,398 control chromosomes in the GnomAD database, including 26,715 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 0.26 (5639 hom., cov: 32)
  • Exomes 𝑓: 0.22 (21076 hom.)
• Consequence: LEPROT NM_017526.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.447
• Publications: 22 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=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPROT	NM_017526.5	c.*349G>A		3_prime_UTR_variant	Exon 4 of 4	ENST00000371065.9	NP_059996.1
LEPR	NM_002303.6	c.-21+6890G>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.*349G>A		3_prime_UTR_variant	Exon 4 of 4	1	NM_017526.5	ENSP00000360104.4
LEPR	ENST00000349533.11	c.-21+6890G>A		intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39288 AN: 151912 Hom.: 5631 Cov.: 32

Gnomad AFR AF: 0.389

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.315

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.235

GnomAD4 exome AF: 0.220 AC: 186898 AN: 848368 Hom.: 21076 Cov.: 31 AF XY: 0.221 AC XY: 86824 AN XY: 393232

African (AFR) AF: 0.405 AC: 6483 AN: 16006

American (AMR) AF: 0.276 AC: 557 AN: 2016

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 1339 AN: 5494

East Asian (EAS) AF: 0.118 AC: 480 AN: 4070

South Asian (SAS) AF: 0.310 AC: 5735 AN: 18510

European-Finnish (FIN) AF: 0.116 AC: 101 AN: 872

Middle Eastern (MID) AF: 0.320 AC: 540 AN: 1686

European-Non Finnish (NFE) AF: 0.214 AC: 165018 AN: 771680

Other (OTH) AF: 0.237 AC: 6645 AN: 28034

GnomAD4 genome AF: 0.259 AC: 39324 AN: 152030 Hom.: 5639 Cov.: 32 AF XY: 0.255 AC XY: 18951 AN XY: 74320

African (AFR) AF: 0.389 AC: 16107 AN: 41426

American (AMR) AF: 0.258 AC: 3938 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 864 AN: 3472

East Asian (EAS) AF: 0.117 AC: 604 AN: 5170

South Asian (SAS) AF: 0.311 AC: 1499 AN: 4822

European-Finnish (FIN) AF: 0.109 AC: 1150 AN: 10578

Middle Eastern (MID) AF: 0.312 AC: 91 AN: 292

European-Non Finnish (NFE) AF: 0.210 AC: 14253 AN: 67974

Other (OTH) AF: 0.237 AC: 500 AN: 2110

Alfa AF: 0.236 Hom.: 3275

Bravo AF: 0.274

Asia WGS AF: 0.219 AC: 765 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.0
DANN	Benign	0.78
PhyloP100		0.45
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: rs7602; hg19: chr1-65897951;