1-65421330-A-C

Variant names:

• chr1-65421330-A-C
• rs12145690
• ENST00000613538.1:c.-87A>C

Variant summary

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

The ENST00000613538.1(LEPROT):​c.-87A>C variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.477 in 1,532,774 control chromosomes in the GnomAD database, including 178,993 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.46 (16920 hom., cov: 32)
  • Exomes 𝑓: 0.48 (162073 hom.)
• Consequence: LEPROT ENST00000613538.1 splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.466
• Publications: 21 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.836 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.-97+590A>C		intron_variant	Intron 1 of 19	ENST00000349533.11	NP_002294.2
LEPROT	NM_017526.5	c.16+590A>C		intron_variant	Intron 1 of 3	ENST00000371065.9	NP_059996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.-97+590A>C		intron_variant	Intron 1 of 19	1	NM_002303.6	ENSP00000330393.7
LEPROT	ENST00000371065.9	c.16+590A>C		intron_variant	Intron 1 of 3	1	NM_017526.5	ENSP00000360104.4

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70597 AN: 151904 Hom.: 16915 Cov.: 32

Gnomad AFR AF: 0.413

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.461

Gnomad ASJ AF: 0.451

Gnomad EAS AF: 0.857

Gnomad SAS AF: 0.588

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.457

Gnomad OTH AF: 0.471

GnomAD4 exome AF: 0.478 AC: 660619 AN: 1380752 Hom.: 162073 Cov.: 34 AF XY: 0.481 AC XY: 327765 AN XY: 681022

African (AFR) AF: 0.410 AC: 12910 AN: 31480

American (AMR) AF: 0.491 AC: 17436 AN: 35508

Ashkenazi Jewish (ASJ) AF: 0.466 AC: 11703 AN: 25100

East Asian (EAS) AF: 0.857 AC: 30585 AN: 35676

South Asian (SAS) AF: 0.577 AC: 45667 AN: 79086

European-Finnish (FIN) AF: 0.479 AC: 16217 AN: 33844

Middle Eastern (MID) AF: 0.462 AC: 2628 AN: 5688

European-Non Finnish (NFE) AF: 0.460 AC: 495430 AN: 1076582

Other (OTH) AF: 0.485 AC: 28043 AN: 57788

GnomAD4 genome AF: 0.465 AC: 70624 AN: 152022 Hom.: 16920 Cov.: 32 AF XY: 0.470 AC XY: 34945 AN XY: 74324

African (AFR) AF: 0.412 AC: 17076 AN: 41450

American (AMR) AF: 0.461 AC: 7049 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 1565 AN: 3470

East Asian (EAS) AF: 0.857 AC: 4424 AN: 5160

South Asian (SAS) AF: 0.589 AC: 2845 AN: 4828

European-Finnish (FIN) AF: 0.475 AC: 5022 AN: 10574

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.457 AC: 31079 AN: 67948

Other (OTH) AF: 0.472 AC: 995 AN: 2106

Alfa AF: 0.466 Hom.: 62479

Bravo AF: 0.459

Asia WGS AF: 0.653 AC: 2273 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.9
DANN	Benign	0.68
PhyloP100		0.47
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12145690; hg19: chr1-65887013;