ENST00000613538.1:c.24G>T

Variant names:

• chr1-65421440-G-T
• rs990285440
• ENST00000613538.1:c.24G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000613538.1(LEPROT):​c.24G>T​(p.Leu8Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,383,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/10 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L8L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LEPROT ENST00000613538.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.530

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.099392146).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.-97+700G>T		intron_variant	Intron 1 of 19	ENST00000349533.11	NP_002294.2
LEPROT	NM_017526.5	c.16+700G>T		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+700G>T		intron_variant	Intron 1 of 19	1	NM_002303.6	ENSP00000330393.7
LEPROT	ENST00000371065.9	c.16+700G>T		intron_variant	Intron 1 of 3	1	NM_017526.5	ENSP00000360104.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000743 AC: 1 AN: 134572 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 73294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000409

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1383816 Hom.: 0 Cov.: 32 AF XY: 0.00000146 AC XY: 1 AN XY: 682852

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	7.1
DANN	Benign	0.81
DEOGEN2	Benign	0.026	T
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.099	T
Sift4G	Uncertain	0.057	T
Vest4		0.20
MVP		0.20
GERP RS		1.6
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs990285440; hg19: chr1-65887123;