Genetic Variant LEPROT:c.*349G>A (chr1-65432268-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_017526.5(LEPROT):c.*349G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,000,398 control chromosomes in the GnomAD database, including 26,715 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.26 ( 5639 hom., cov: 32)

Exomes 𝑓: 0.22 ( 21076 hom. )

Consequence

LEPROT
NM_017526.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.447

Publications

22 publications found

Variant links:

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]

LEPROT links:

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: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

LEPR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPROT	NM_017526.5 link	c.*349G>A		3_prime_UTR_variant	Exon 4 of 4	ENST00000371065.9	NP_059996.1	O15243
LEPR	NM_002303.6 link	c.-21+6890G>A		intron_variant	Intron 2 of 19	ENST00000349533.11	NP_002294.2	P48357-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPROT	ENST00000371065.9 link	c.*349G>A		3_prime_UTR_variant	Exon 4 of 4	1	NM_017526.5	ENSP00000360104.4		O15243
LEPR	ENST00000349533.11 link	c.-21+6890G>A		intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7		P48357-1

Frequencies

GnomAD3 genomes

AF:

0.259

AC:

39288

AN:

151912

Hom.:

5631

Cov.:

show subpopulations

Gnomad AFR

AF:

0.389

Gnomad AMI

AF:

0.349

Gnomad AMR

AF:

0.258

Gnomad ASJ

AF:

0.249

Gnomad EAS

AF:

0.117

Gnomad SAS

AF:

0.310

Gnomad FIN

AF:

0.109

Gnomad MID

AF:

0.315

Gnomad NFE

AF:

0.210

Gnomad OTH

AF:

0.235

GnomAD4 exome

AF:

0.220

AC:

186898

AN:

848368

Hom.:

21076

Cov.:

AF XY:

0.221

AC XY:

86824

AN XY:

393232

show subpopulations

African (AFR)

AF:

0.405

AC:

6483

AN:

16006

American (AMR)

AF:

0.276

AC:

557

AN:

2016

Ashkenazi Jewish (ASJ)

AF:

0.244

AC:

1339

AN:

5494

East Asian (EAS)

AF:

0.118

AC:

480

AN:

4070

South Asian (SAS)

AF:

0.310

AC:

5735

AN:

18510

European-Finnish (FIN)

AF:

0.116

AC:

101

AN:

872

Middle Eastern (MID)

AF:

0.320

AC:

540

AN:

1686

European-Non Finnish (NFE)

AF:

0.214

AC:

165018

AN:

771680

Other (OTH)

AF:

0.237

AC:

6645

AN:

28034

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

7300

14601

21901

29202

36502

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7818

15636

23454

31272

39090

<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:

0.259

AC:

39324

AN:

152030

Hom.:

5639

Cov.:

AF XY:

0.255

AC XY:

18951

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.389

AC:

16107

AN:

41426

American (AMR)

AF:

0.258

AC:

3938

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.249

AC:

864

AN:

3472

East Asian (EAS)

AF:

0.117

AC:

604

AN:

5170

South Asian (SAS)

AF:

0.311

AC:

1499

AN:

4822

European-Finnish (FIN)

AF:

0.109

AC:

1150

AN:

10578

Middle Eastern (MID)

AF:

0.312

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.210

AC:

14253

AN:

67974

Other (OTH)

AF:

0.237

AC:

500

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1424

2848

4273

5697

7121

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

404

808

1212

1616

2020

<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:

0.236

Hom.:

3275

Bravo

AF:

0.274

Asia WGS

AF:

0.219

AC:

765

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

4.0

(source)

DANN

Benign

0.78

PhyloP100

0.45

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over