rs587777699

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_ModeratePP5

The NM_005357.4(LIPE):c.3203_3221delTAGACGGGGGCTGCGGGGG(p.Val1068GlyfsTer102) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000566 in 151,870 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00047 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

LIPE
NM_005357.4 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 1.87

Publications

7 publications found

Variant links:

Genes affected

LIPE (HGNC:6621): (lipase E, hormone sensitive type) The protein encoded by this gene has a long and a short form, generated by use of alternative translational start codons. The long form is expressed in steroidogenic tissues such as testis, where it converts cholesteryl esters to free cholesterol for steroid hormone production. The short form is expressed in adipose tissue, among others, where it hydrolyzes stored triglycerides to free fatty acids. [provided by RefSeq, Jul 2008]

LIPE links:

LIPE-AS1 (HGNC:48589): (LIPE antisense RNA 1)

LIPE-AS1 links:

LOC101930071 (HGNC:):

LOC101930071 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00867 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PP5

Variant 19-42401821-CCCCCCGCAGCCCCCGTCTA-C is Pathogenic according to our data. Variant chr19-42401821-CCCCCCGCAGCCCCCGTCTA-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 155901.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPE	NM_005357.4 link	c.3203_3221delTAGACGGGGGCTGCGGGGG	p.Val1068GlyfsTer102	frameshift_variant	Exon 10 of 10	ENST00000244289.9	NP_005348.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIPE	ENST00000244289.9 link	c.3203_3221delTAGACGGGGGCTGCGGGGG	p.Val1068GlyfsTer102	frameshift_variant	Exon 10 of 10	1	NM_005357.4	ENSP00000244289.3

Frequencies

GnomAD3 genomes

AF:

0.000567

AC:

AN:

151760

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.0242

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00289

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.000837

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000442

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000798

AC:

AN:

83980

AF XY:

0.000979

show subpopulations

Gnomad AFR exome

AF:

0.000919

Gnomad AMR exome

AF:

0.000671

Gnomad ASJ exome

AF:

0.00265

Gnomad EAS exome

AF:

0.000286

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000759

Gnomad OTH exome

AF:

0.00124

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000467

AC:

620

AN:

1327478

Hom.:

AF XY:

0.000463

AC XY:

302

AN XY:

652232

show subpopulations

African (AFR)

AF:

0.000395

AC:

AN:

27834

American (AMR)

AF:

0.000491

AC:

AN:

26476

Ashkenazi Jewish (ASJ)

AF:

0.00152

AC:

AN:

21112

East Asian (EAS)

AF:

0.000269

AC:

AN:

33466

South Asian (SAS)

AF:

0.000658

AC:

AN:

69908

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40308

Middle Eastern (MID)

AF:

0.00131

AC:

AN:

3804

European-Non Finnish (NFE)

AF:

0.000458

AC:

481

AN:

1049456

Other (OTH)

AF:

0.000417

AC:

AN:

55114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.566

Heterozygous variant carriers

121

151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000566

AC:

AN:

151870

Hom.:

Cov.:

AF XY:

0.000526

AC XY:

AN XY:

74180

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41412

American (AMR)

AF:

0.000327

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00289

AC:

AN:

3466

East Asian (EAS)

AF:

0.000388

AC:

AN:

5152

South Asian (SAS)

AF:

0.000838

AC:

AN:

4776

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10558

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000442

AC:

AN:

67916

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.544

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000622

Hom.:

Bravo

AF:

0.000676

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

LIPE-related familial partial lipodystrophy

Pathogenic:4Uncertain:1

Jun 12, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 01, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LIPE c.3203_3221del19 (p.Val1068GlyfsX102) causes a frameshift which results in an extension of the protein and is not expected to undergo nonsense mediated decay. The variant allele was found at a frequency of 0.00048 in 1479348 control chromosomes in the gnomAD database, including 1 homozygote. Notably, it is found at a frequency of 0.024 within individuals of Amish ancestry. c.3203_3221del19 has been reported in the literature in the homozygous state in four siblings with clinical features of LIPE-Related Familial Partial Lipodystrophy from an Old Order Amish family where the variant primarily segregated with the disease phenotype amongst a total of ten siblings (Albert_2014). The variant has also been reported either in the heterozygous state or as an uninformative genotype in at least two other individuals with low HDL cholesterol/dyslipidemia who underwent WES/multigene panel testing (e.g. Dron_2020, Dong_2022). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Albert_2014). In vitro, the variant was not found to significantly affect mRNA expression, but resulted in reduced protein levels. Additionally, in subcutaneous abdominal adipocytes from homozygous individuals, no protein was detected and triglyceride lipase activity and cholesterol ester hydrolase activity were reduced compared to wild type individuals and heterozygous carriers. The following publications have been ascertained in the context of this evaluation (PMID: 24848981, 35460704, 32041611). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Mar 24, 2023

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 28, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jun 02, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

LIPE-related disorder

Pathogenic:1

Jun 20, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The LIPE c.3203_3221del19 variant is predicted to result in a frameshift and premature protein termination (p.Val1068Glyfs*102). This variant has been reported in the homozygous state in four siblings from an Amish community with partial lipodystrophy (p.V767Gfs*102 in Albert et al. 2014. PubMed ID: 24848981). Albert et al. also found that heterozygous individuals did not display the same adipose-tissue dysfunction as homozygous individuals; however, they did present with a range of features including dyslipidemia, hepatic steatosis, and diabetes (Albert et al. 2014. PubMed ID: 24848981). In addition, other studies have suggested that this variant leads to an increased risk of hypertriglyceridemia and other types of dyslipidemia when found in the heterozygous state (Table S2 in Deshotels et al. 2022. PubMed ID: 36325899; Table S4 in Dron et al. 2020. PubMed ID: 32041611). Familial segregation data and biochemical studies support its pathogenicity (Albert et al. 2014. PubMed ID: 24848981). This variant is reported in 0.27% of alleles in individuals of Ashkenazi Jewish descent in gnomAD; however, the quality of the data at this position is questionable and should be interpreted with caution. Frameshift variants in LIPE are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.9

Mutation Taster

=45/155

disease causing (ClinVar)

(source)

Splicing

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over