19-42401821-CCCCCCGCAGCCCCCGTCTA-CCCCCCGCAGCCCCCGTCTACCCCCGCAGCCCCCGTCTACCCCCGCAGCCCCCGTCTA

Variant names:

• chr19-42401821-C-CCCCCCGCAGCCCCCGTCTACCCCCGCAGCCCCCGTCTA
• rs587777699
• NM_005357.4:c.3221_3222insTAGACGGGGGCTGCGGGGGTAGACGGGGGCTGCGGGGG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_005357.4(LIPE):​c.3221_3222insTAGACGGGGGCTGCGGGGGTAGACGGGGGCTGCGGGGG​(p.His1076ArgfsTer6) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000218 in 1,328,322 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 INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000022 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LIPE NM_005357.4 frameshift, stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.38
• Publications: 0 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 2 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 0.0031 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

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.3221_3222insTAGACGGGGGCTGCGGGGGTAGACGGGGGCTGCGGGGG	p.His1076ArgfsTer6	frameshift stop_gained	Exon 10 of 10	NP_005348.2
	LIPE	NM_001416100.1		c.2471_2472insTAGACGGGGGCTGCGGGGGTAGACGGGGGCTGCGGGGG	p.His826ArgfsTer6	frameshift stop_gained	Exon 10 of 10	NP_001403029.1
	LIPE	NM_001416101.1		c.2456_2457insTAGACGGGGGCTGCGGGGGTAGACGGGGGCTGCGGGGG	p.His821ArgfsTer6	frameshift stop_gained	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.3221_3222insTAGACGGGGGCTGCGGGGGTAGACGGGGGCTGCGGGGG	p.His1076ArgfsTer6	frameshift stop_gained	Exon 10 of 10	ENSP00000244289.3	Q05469-1
	LIPE-AS1	ENST00000594624.8	TSL:1	n.105+4634_105+4635insACCCCCGCAGCCCCCGTCTACCCCCGCAGCCCCCGTCT		intron	N/A
	LIPE	ENST00000599918.2	TSL:5	c.3245_3246insTAGACGGGGGCTGCGGGGGTAGACGGGGGCTGCGGGGG	p.His1084ArgfsTer6	frameshift stop_gained	Exon 10 of 10	ENSP00000472218.2	M0R201

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151792 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00105

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000218 AC: 29 AN: 1328322 Hom.: 0 Cov.: 30 AF XY: 0.0000291 AC XY: 19 AN XY: 652594

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27848

American (AMR) AF: 0.00 AC: 0 AN: 26492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21122

East Asian (EAS) AF: 0.00 AC: 0 AN: 33480

South Asian (SAS) AF: 0.000401 AC: 28 AN: 69894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3806

European-Non Finnish (NFE) AF: 9.52e-7 AC: 1 AN: 1050218

Other (OTH) AF: 0.00 AC: 0 AN: 55152

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000395 AC: 6 AN: 151900 Hom.: 0 Cov.: 30 AF XY: 0.0000539 AC XY: 4 AN XY: 74192

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00105 AC: 5 AN: 4776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67930

Other (OTH) AF: 0.00 AC: 0 AN: 2114

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00169570), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=112/88	polymorphism

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;