rs1045895

Variant names:

• chr1-65432298-G-A
• rs1045895
• NM_017526.5:c.*379G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-65432298-G-A
• chr1-65432298-G-T

Variant summary

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

The NM_017526.5(LEPROT):​c.*379G>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 0.362 in 993,224 control chromosomes in the GnomAD database, including 69,079 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 0.27 (7201 hom., cov: 31)
  • Exomes 𝑓: 0.38 (61878 hom.)
• Consequence: LEPROT NM_017526.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14
• Publications: 30 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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.381 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPROT	NM_017526.5	c.*379G>A		3_prime_UTR_variant	Exon 4 of 4	ENST00000371065.9	NP_059996.1
LEPR	NM_002303.6	c.-21+6920G>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.*379G>A		3_prime_UTR_variant	Exon 4 of 4	1	NM_017526.5	ENSP00000360104.4
LEPR	ENST00000349533.11	c.-21+6920G>A		intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41344 AN: 151872 Hom.: 7204 Cov.: 31

Gnomad AFR AF: 0.0734

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.397

Gnomad EAS AF: 0.0249

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.318

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.320

GnomAD4 exome AF: 0.378 AC: 318068 AN: 841234 Hom.: 61878 Cov.: 32 AF XY: 0.379 AC XY: 147706 AN XY: 389248

African (AFR) AF: 0.0468 AC: 743 AN: 15878

American (AMR) AF: 0.332 AC: 555 AN: 1672

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 2142 AN: 5274

East Asian (EAS) AF: 0.0230 AC: 89 AN: 3864

South Asian (SAS) AF: 0.226 AC: 3948 AN: 17458

European-Finnish (FIN) AF: 0.348 AC: 207 AN: 594

Middle Eastern (MID) AF: 0.323 AC: 533 AN: 1650

European-Non Finnish (NFE) AF: 0.392 AC: 300409 AN: 767158

Other (OTH) AF: 0.341 AC: 9442 AN: 27686

GnomAD4 genome AF: 0.272 AC: 41334 AN: 151990 Hom.: 7201 Cov.: 31 AF XY: 0.266 AC XY: 19777 AN XY: 74280

African (AFR) AF: 0.0732 AC: 3038 AN: 41514

American (AMR) AF: 0.335 AC: 5100 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.397 AC: 1376 AN: 3468

East Asian (EAS) AF: 0.0252 AC: 130 AN: 5162

South Asian (SAS) AF: 0.216 AC: 1038 AN: 4816

European-Finnish (FIN) AF: 0.318 AC: 3345 AN: 10522

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.385 AC: 26176 AN: 67948

Other (OTH) AF: 0.317 AC: 668 AN: 2110

Alfa AF: 0.344 Hom.: 23663

Bravo AF: 0.269

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.2
DANN	Benign	0.73
PhyloP100		1.1
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: rs1045895; hg19: chr1-65897981;