dbSNP rs1805096: LEPR:p.Pro1019Pro (chr1-65636574-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002303.6(LEPR):c.3057G>A(p.Pro1019Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 1,613,714 control chromosomes in the GnomAD database, including 139,816 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1019P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.44 ( 15242 hom., cov: 32)

Exomes 𝑓: 0.40 ( 124574 hom. )

Consequence

LEPR
NM_002303.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.823

Publications

120 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP6

Variant 1-65636574-G-A is Benign according to our data. Variant chr1-65636574-G-A is described in ClinVar as Benign. ClinVar VariationId is 298000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.823 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.849 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	NM_002303.6	MANE Select	c.3057G>A	p.Pro1019Pro	synonymous	Exon 20 of 20	NP_002294.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.3057G>A	p.Pro1019Pro	synonymous	Exon 20 of 20	ENSP00000330393.7	P48357-1

Frequencies

GnomAD3 genomes

AF:

0.437

AC:

66340

AN:

151842

Hom.:

15210

Cov.:

show subpopulations

Gnomad AFR

AF:

0.451

Gnomad AMI

AF:

0.330

Gnomad AMR

AF:

0.472

Gnomad ASJ

AF:

0.376

Gnomad EAS

AF:

0.870

Gnomad SAS

AF:

0.464

Gnomad FIN

AF:

0.496

Gnomad MID

AF:

0.339

Gnomad NFE

AF:

0.382

Gnomad OTH

AF:

0.416

GnomAD2 exomes

AF:

0.457

AC:

114099

AN:

249416

AF XY:

0.452

show subpopulations

Gnomad AFR exome

AF:

0.453

Gnomad AMR exome

AF:

0.507

Gnomad ASJ exome

AF:

0.374

Gnomad EAS exome

AF:

0.873

Gnomad FIN exome

AF:

0.484

Gnomad NFE exome

AF:

0.377

Gnomad OTH exome

AF:

0.425

GnomAD4 exome

AF:

0.403

AC:

589205

AN:

1461754

Hom.:

124574

Cov.:

AF XY:

0.404

AC XY:

293419

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.453

AC:

15161

AN:

33472

American (AMR)

AF:

0.500

AC:

22328

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.381

AC:

9963

AN:

26128

East Asian (EAS)

AF:

0.868

AC:

34468

AN:

39694

South Asian (SAS)

AF:

0.464

AC:

40011

AN:

86252

European-Finnish (FIN)

AF:

0.479

AC:

25556

AN:

53386

Middle Eastern (MID)

AF:

0.361

AC:

2080

AN:

5768

European-Non Finnish (NFE)

AF:

0.373

AC:

414616

AN:

1111962

Other (OTH)

AF:

0.414

AC:

25022

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

22928

45856

68784

91712

114640

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13278

26556

39834

53112

66390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.437

AC:

66434

AN:

151960

Hom.:

15242

Cov.:

AF XY:

0.446

AC XY:

33101

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.451

AC:

18697

AN:

41432

American (AMR)

AF:

0.472

AC:

7205

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.376

AC:

1304

AN:

3464

East Asian (EAS)

AF:

0.870

AC:

4495

AN:

5168

South Asian (SAS)

AF:

0.462

AC:

2226

AN:

4818

European-Finnish (FIN)

AF:

0.496

AC:

5238

AN:

10552

Middle Eastern (MID)

AF:

0.364

AC:

107

AN:

294

European-Non Finnish (NFE)

AF:

0.382

AC:

25966

AN:

67948

Other (OTH)

AF:

0.423

AC:

895

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1861

3722

5582

7443

9304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

616

1232

1848

2464

3080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.400

Hom.:

54603

Bravo

AF:

0.436

Asia WGS

AF:

0.624

AC:

2165

AN:

3478

EpiCase

AF:

0.373

EpiControl

AF:

0.377

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Obesity due to leptin receptor gene deficiency (3)

not specified (2)

Monogenic Non-Syndromic Obesity (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.33

(source)

DANN

Benign

0.34

PhyloP100

-0.82

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over