rs1646455417

Variant names:

• chr1-65429999-T-C
• rs1646455417
• NM_017526.5:c.230T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_017526.5(LEPROT):​c.230T>C​(p.Ile77Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000508 in 1,573,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: LEPROT NM_017526.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017526.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPROT	NM_017526.5	MANE Select	c.230T>C	p.Ile77Thr	missense	Exon 3 of 4	NP_059996.1	O15243
	LEPR	NM_002303.6	MANE Select	c.-21+4621T>C		intron	N/A	NP_002294.2
	LEPROT	NM_001198681.2		c.257T>C	p.Ile86Thr	missense	Exon 4 of 5	NP_001185610.1	A0A087X0N2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPROT	ENST00000371065.9	TSL:1 MANE Select	c.230T>C	p.Ile77Thr	missense	Exon 3 of 4	ENSP00000360104.4	O15243
	LEPROT	ENST00000613538.1	TSL:1	c.257T>C	p.Ile86Thr	missense	Exon 4 of 5	ENSP00000483521.1	A0A087X0N2
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.-21+4621T>C		intron	N/A	ENSP00000330393.7	P48357-1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000281 AC: 4 AN: 1421464 Hom.: 0 Cov.: 30 AF XY: 0.00000428 AC XY: 3 AN XY: 701594

African (AFR) AF: 0.00 AC: 0 AN: 32906

American (AMR) AF: 0.00 AC: 0 AN: 44024

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25458

East Asian (EAS) AF: 0.00 AC: 0 AN: 38690

South Asian (SAS) AF: 0.0000482 AC: 4 AN: 82960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5636

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081162

Other (OTH) AF: 0.00 AC: 0 AN: 58244

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.86	P
Vest4		0.93
MutPred		0.70		Loss of stability (P = 0.0489)
MVP		0.33
MPC		0.92
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.93
Mutation Taster		=19/81	disease causing

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: rs1646455417; hg19: chr1-65895682;