rs587777699

Variant names:

• chr19-42401821-CCCCCCGCAGCCCCCGTCTA-C
• rs587777699
• NM_005357.4:c.3203_3221delTAGACGGGGGCTGCGGGGG

Your query was ambiguous. Multiple possible variants found:

• chr19-42401821-CCCCCCGCAGCCCCCGTCTA-C
• chr19-42401821-CCCCCCGCAGCCCCCGTCTA-CCCCCCGCAGCCCCCGTCTACCCCCGCAGCCCCCGTCTA
• chr19-42401821-CCCCCCGCAGCCCCCGTCTA-CCCCCCGCAGCCCCCGTCTACCCCCGCAGCCCCCGTCTACCCCCGCAGCCCCCGTCTA
• chr19-42401821-CCCCCCGCAGCCCCCGTCTA-CCCCCCGCAGCCCCCGTCTACCCCCGCAGCCCCCGTCTACCCCCGCAGCCCCCGTCTACCCCCGCAGCCCCCGTCTA

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Moderate PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 1.87
• Publications: 7 publications found

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

LOC101930071 (HGNC:):

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005357.4. 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
	LIPE	NM_005357.4	MANE Select	c.3203_3221delTAGACGGGGGCTGCGGGGG	p.Val1068GlyfsTer102	frameshift	Exon 10 of 10	NP_005348.2
	LIPE	NM_001416100.1		c.2453_2471delTAGACGGGGGCTGCGGGGG	p.Val818GlyfsTer102	frameshift	Exon 10 of 10	NP_001403029.1
	LIPE	NM_001416101.1		c.2438_2456delTAGACGGGGGCTGCGGGGG	p.Val813GlyfsTer102	frameshift	Exon 10 of 10	NP_001403030.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPE	ENST00000244289.9	TSL:1 MANE Select	c.3203_3221delTAGACGGGGGCTGCGGGGG	p.Val1068GlyfsTer102	frameshift	Exon 10 of 10	ENSP00000244289.3	Q05469-1
	LIPE-AS1	ENST00000594624.8	TSL:1	n.105+4616_105+4634delACCCCCGCAGCCCCCGTCT		intron	N/A
	LIPE	ENST00000599918.2	TSL:5	c.3227_3245delTAGACGGGGGCTGCGGGGG	p.Val1076GlyfsTer3	frameshift	Exon 10 of 10	ENSP00000472218.2	M0R201

Frequencies

GnomAD3 genomes AF: 0.000567 AC: 86 AN: 151760 Hom.: 0 Cov.: 30

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: 67 AN: 83980 AF XY: 0.000979

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.: 1 AF XY: 0.000463 AC XY: 302 AN XY: 652232

African (AFR) AF: 0.000395 AC: 11 AN: 27834

American (AMR) AF: 0.000491 AC: 13 AN: 26476

Ashkenazi Jewish (ASJ) AF: 0.00152 AC: 32 AN: 21112

East Asian (EAS) AF: 0.000269 AC: 9 AN: 33466

South Asian (SAS) AF: 0.000658 AC: 46 AN: 69908

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40308

Middle Eastern (MID) AF: 0.00131 AC: 5 AN: 3804

European-Non Finnish (NFE) AF: 0.000458 AC: 481 AN: 1049456

Other (OTH) AF: 0.000417 AC: 23 AN: 55114

GnomAD4 genome AF: 0.000566 AC: 86 AN: 151870 Hom.: 0 Cov.: 30 AF XY: 0.000526 AC XY: 39 AN XY: 74180

African (AFR) AF: 0.000241 AC: 10 AN: 41412

American (AMR) AF: 0.000327 AC: 5 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00289 AC: 10 AN: 3466

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5152

South Asian (SAS) AF: 0.000838 AC: 4 AN: 4776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000442 AC: 30 AN: 67916

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000622 Hom.: 1

Bravo AF: 0.000676

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	1	-	LIPE-related familial partial lipodystrophy (5)
1	-	-	LIPE-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=45/155	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587777699; hg19: chr19-42905973; COSMIC: COSV54921928; COSMIC: COSV54921928;