Variant 1-65565568-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_002303.6(LEPR):c.3G>A(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

LEPR
NM_002303.6 start_lost

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.71

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-65565568-G-A is Pathogenic according to our data. Variant chr1-65565568-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3357044.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPR	NM_002303.6 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	3/20	ENST00000349533.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPR	ENST00000349533.11 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	3/20	1	NM_002303.6	P4	P48357-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

LEPR-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 02, 2024

The LEPR c.3G>A variant is predicted to disrupt the translation initiation site (Start Loss). This variant has been reported in the homozygous state in an individual with severe obesity (Courbage et al. 2021. PubMed ID: 34097736). A different start loss variant ( c.2T>C) has also been reported in the homozygous state in an individual with severe obesity (Saeed et al. 2020. PubMed ID: 32349990). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Uncertain

0.11

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.092

.;.;T;.;.;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

D;.;D;D;D;.

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D

MetaSVM

Benign

-0.46

MutationTaster

Benign

1.0

D;D;D;D;D;D

PROVEAN

Benign

-1.3

N;N;N;N;.;N

REVEL

Benign

0.27

Sift

Pathogenic

0.0

D;D;D;D;.;D

Sift4G

Uncertain

0.029

D;D;D;D;D;D

Polyphen

0.46

P;P;P;D;P;D

Vest4

0.82

MutPred

0.87

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);

MVP

0.87

ClinPred

0.99

GERP RS

5.4

Varity_R

0.83

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.33

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.33

Position offset: -22

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over