Genetic Variant LEPR:p.Trp31Cys (chr1-65570525-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_002303.6(LEPR):c.93G>T(p.Trp31Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Consequence

LEPR
NM_002303.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.51

Publications

0 publications found

Variant links:

Genes affected

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

LEPR links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002303.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LEPR	NM_002303.6	MANE Select	c.93G>T	p.Trp31Cys	missense	Exon 4 of 20	NP_002294.2
LEPR	NM_001003680.3		c.93G>T	p.Trp31Cys	missense	Exon 4 of 20	NP_001003680.1	P48357-3
LEPR	NM_001198687.2		c.93G>T	p.Trp31Cys	missense	Exon 3 of 19	NP_001185616.1	P48357-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LEPR	ENST00000349533.11	TSL:1 MANE Select	c.93G>T	p.Trp31Cys	missense	Exon 4 of 20	ENSP00000330393.7	P48357-1
LEPR	ENST00000371059.7	TSL:1	c.93G>T	p.Trp31Cys	missense	Exon 4 of 20	ENSP00000360098.3	P48357-3
LEPR	ENST00000344610.12	TSL:1	c.93G>T	p.Trp31Cys	missense	Exon 3 of 19	ENSP00000340884.8	P48357-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.033

MetaRNN

Uncertain

0.69

MetaSVM

Benign

-0.54

MutationAssessor

Uncertain

2.3

PhyloP100

3.5

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-4.3

REVEL

Uncertain

0.35

Sift

Uncertain

0.011

Sift4G

Uncertain

0.024

Polyphen

1.0

Vest4

0.61

MutPred

0.63

Loss of sheet (P = 0.0315)

MVP

0.52

MPC

0.61

ClinPred

0.99

GERP RS

5.6

Varity_R

0.32

gMVP

0.89

Mutation Taster

=265/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.90

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.90

Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over