NM_000230.3:c.-29+2336T>A

Variant names:

Germline classification Cancer classification (beta)

Variant summary

Our verdict is . The variant received -12 ACMG points: 0P and 12B. BA1BP4_Strong

The NM_000230.3(LEP):c.-29+2336T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.906 (AC=137,861) in the gnomAD database across 152,202 control chromosomes, including 62,667 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.93. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.91 ( 62667 hom., cov: 32)

Consequence

LEP
NM_000230.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.282

Publications

7 publications found

Variant links:

Genes affected

LEP (HGNC:6553): (leptin) This gene encodes a protein that is secreted by white adipocytes into the circulation and plays a major role in the regulation of energy homeostasis. Circulating leptin binds to the leptin receptor in the brain, which activates downstream signaling pathways that inhibit feeding and promote energy expenditure. This protein also has several endocrine functions, and is involved in the regulation of immune and inflammatory responses, hematopoiesis, angiogenesis, reproduction, bone formation and wound healing. Mutations in this gene and its regulatory regions cause severe obesity and morbid obesity with hypogonadism in human patients. A mutation in this gene has also been linked to type 2 diabetes mellitus development. [provided by RefSeq, Aug 2017]

LEP Gene-Disease associations (from GenCC):

obesity due to congenital leptin deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, PanelApp Australia, Genomics England PanelApp

LEP links:

ENSG00000289434 (HGNC:):

ENSG00000289434 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000230.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

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

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.9305 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000230.3. 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
	LEP	NM_000230.3	MANE Select	c.-29+2336T>A		intron	N/A	NP_000221.1	P41159

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LEP	ENST00000308868.5	TSL:1 MANE Select	c.-29+2336T>A	intron	N/A	ENSP00000312652.4	P41159
LEP	ENST00000965599.1		c.-29+2336T>A	intron	N/A	ENSP00000635658.1
ENSG00000289434	ENST00000785131.1		n.168+19720A>T	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.906

AC:

137759

AN:

152084

Hom.:

62621

Cov.:

show subpopulations

Gnomad AFR

AF:

0.828

Gnomad AMI

AF:

0.997

Gnomad AMR

AF:

0.943

Gnomad ASJ

AF:

0.912

Gnomad EAS

AF:

0.946

Gnomad SAS

AF:

0.927

Gnomad FIN

AF:

0.926

Gnomad MID

AF:

0.975

Gnomad NFE

AF:

0.935

Gnomad OTH

AF:

0.921

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

GnomAD4 genome

AF:

0.906

AC:

137861

AN:

152202

Hom.:

62667

Cov.:

AF XY:

0.908

AC XY:

67540

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.828

AC:

34370

AN:

41504

American (AMR)

AF:

0.943

AC:

14441

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.912

AC:

3165

AN:

3472

East Asian (EAS)

AF:

0.946

AC:

4895

AN:

5176

South Asian (SAS)

AF:

0.926

AC:

4465

AN:

4820

European-Finnish (FIN)

AF:

0.926

AC:

9815

AN:

10602

Middle Eastern (MID)

AF:

0.973

AC:

286

AN:

294

European-Non Finnish (NFE)

AF:

0.935

AC:

63568

AN:

68000

Other (OTH)

AF:

0.921

AC:

1947

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

672

1343

2015

2686

3358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

904

1808

2712

3616

4520

<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:

0.916

Hom.:

7948

Bravo

AF:

0.906

Asia WGS

AF:

0.936

AC:

3255

AN:

3478

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.949

AC:

116549

AN:

122812

Turkish Variome

AF:

0.944

AC:

1457

AN:

1544

Hom.:

687

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.957

AC:

8577

AN:

8960

Hom.:

4107

ABraOM SABE-WGS-1171

AF:

0.927

AC:

2172

AN:

2342

Hom.:

1008

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

9.7

(source)

DANN

Benign

0.80

PhyloP100

0.28

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over