dbSNP rs6673324: LEPR:c.-20-166G>A (chr1-65565380-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_002303.6(LEPR):c.-20-166G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 151,976 control chromosomes in the GnomAD database, including 21,607 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.53 ( 21607 hom., cov: 32)

Consequence

LEPR
NM_002303.6 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.571

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BP6

Variant 1-65565380-G-A is Benign according to our data. Variant chr1-65565380-G-A is described in ClinVar as [Benign]. Clinvar id is 1235035.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6 link	c.-20-166G>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
LEPR	ENST00000349533.11 link	c.-20-166G>A		intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7		P48357-1

Frequencies

GnomAD3 genomes

AF:

0.525

AC:

79719

AN:

151856

Hom.:

21583

Cov.:

show subpopulations

Gnomad AFR

AF:

0.520

Gnomad AMI

AF:

0.324

Gnomad AMR

AF:

0.446

Gnomad ASJ

AF:

0.475

Gnomad EAS

AF:

0.890

Gnomad SAS

AF:

0.490

Gnomad FIN

AF:

0.636

Gnomad MID

AF:

0.362

Gnomad NFE

AF:

0.510

Gnomad OTH

AF:

0.500

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.525

AC:

79793

AN:

151976

Hom.:

21607

Cov.:

AF XY:

0.529

AC XY:

39274

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.519

AC:

21521

AN:

41428

American (AMR)

AF:

0.446

AC:

6815

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.475

AC:

1648

AN:

3466

East Asian (EAS)

AF:

0.890

AC:

4612

AN:

5184

South Asian (SAS)

AF:

0.490

AC:

2359

AN:

4816

European-Finnish (FIN)

AF:

0.636

AC:

6716

AN:

10556

Middle Eastern (MID)

AF:

0.373

AC:

109

AN:

292

European-Non Finnish (NFE)

AF:

0.510

AC:

34654

AN:

67942

Other (OTH)

AF:

0.505

AC:

1064

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1883

3766

5649

7532

9415

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.503

Hom.:

10025

Bravo

AF:

0.510

Asia WGS

AF:

0.670

AC:

2323

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.083

(source)

DANN

Benign

0.64

PhyloP100

-0.57

PromoterAI

-0.0092

Neutral

(source)

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

LitVar

Below is the list of publications found by LitVar for variant 1:65565380 G>A . It may be empty.

rs6673324

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over