Genetic Variant LEPR:c.-20-15A>T (chr1-65565531-A-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002303.6(LEPR):c.-20-15A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00649 in 1,613,526 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0046 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0067 ( 33 hom. )

Consequence

LEPR
NM_002303.6 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.439

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 1-65565531-A-T is Benign according to our data. Variant chr1-65565531-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 297985.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00456 (694/152212) while in subpopulation NFE AF = 0.00684 (465/67994). AF 95% confidence interval is 0.00632. There are 10 homozygotes in GnomAd4. There are 285 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

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	Effect	Exon Rank	Protein	UniProt
LEPR	NM_002303.6	MANE Select	c.-20-15A>T	intron	N/A	NP_002294.2
LEPR	NM_001003680.3		c.-20-15A>T	intron	N/A	NP_001003680.1	P48357-3
LEPR	NM_001198687.2		c.-20-15A>T	intron	N/A	NP_001185616.1	P48357-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LEPR	ENST00000349533.11	TSL:1 MANE Select	c.-20-15A>T	intron	N/A	ENSP00000330393.7	P48357-1
LEPR	ENST00000371059.7	TSL:1	c.-20-15A>T	intron	N/A	ENSP00000360098.3	P48357-3
LEPR	ENST00000344610.12	TSL:1	c.-20-15A>T	intron	N/A	ENSP00000340884.8	P48357-4

Frequencies

GnomAD3 genomes

AF:

0.00456

AC:

694

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.0779

Gnomad AMR

AF:

0.00282

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00684

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00411

AC:

1031

AN:

250884

AF XY:

0.00438

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00211

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00176

Gnomad NFE exome

AF:

0.00611

Gnomad OTH exome

AF:

0.00409

GnomAD4 exome

AF:

0.00670

AC:

9785

AN:

1461314

Hom.:

Cov.:

AF XY:

0.00660

AC XY:

4801

AN XY:

726950

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

33462

American (AMR)

AF:

0.00208

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00184

AC:

AN:

26110

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39600

South Asian (SAS)

AF:

0.00564

AC:

486

AN:

86212

European-Finnish (FIN)

AF:

0.00187

AC:

100

AN:

53382

Middle Eastern (MID)

AF:

0.00451

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00778

AC:

8646

AN:

1111708

Other (OTH)

AF:

0.00572

AC:

345

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

474

948

1423

1897

2371

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

336

672

1008

1344

1680

<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:

0.00456

AC:

694

AN:

152212

Hom.:

Cov.:

AF XY:

0.00383

AC XY:

285

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00135

AC:

AN:

41538

American (AMR)

AF:

0.00281

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00519

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00160

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00684

AC:

465

AN:

67994

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

122

152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00270

Hom.:

Bravo

AF:

0.00466

Asia WGS

AF:

0.00173

AC:

AN:

3474

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Monogenic Non-Syndromic Obesity (1)

not provided (1)

Obesity due to leptin receptor gene deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

(source)

DANN

Benign

0.68

PhyloP100

0.44

PromoterAI

-0.0054

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(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