19-42401821-C-CCCCCCGCAGCCCCCGTCTA

Variant names:

• chr19-42401821-C-CCCCCCGCAGCCCCCGTCTA
• rs587777699
• NM_005357.4:c.3203_3221dupTAGACGGGGGCTGCGGGGG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PVS1_Moderate BS2

The NM_005357.4(LIPE):​c.3203_3221dupTAGACGGGGGCTGCGGGGG​(p.His1076ArgfsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,480,228 control chromosomes in the GnomAD database, including 2 homozygotes. 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: LIPE NM_005357.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38
• 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: Likely_benign. 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.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPE	NM_005357.4	MANE Select	c.3203_3221dupTAGACGGGGGCTGCGGGGG	p.His1076ArgfsTer21	frameshift	Exon 10 of 10	NP_005348.2
	LIPE	NM_001416100.1		c.2453_2471dupTAGACGGGGGCTGCGGGGG	p.His826ArgfsTer21	frameshift	Exon 10 of 10	NP_001403029.1
	LIPE	NM_001416101.1		c.2438_2456dupTAGACGGGGGCTGCGGGGG	p.His821ArgfsTer21	frameshift	Exon 10 of 10	NP_001403030.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPE	ENST00000244289.9	TSL:1 MANE Select	c.3203_3221dupTAGACGGGGGCTGCGGGGG	p.His1076ArgfsTer21	frameshift	Exon 10 of 10	ENSP00000244289.3
	LIPE-AS1	ENST00000594624.8	TSL:1	n.105+4616_105+4634dupACCCCCGCAGCCCCCGTCT		intron	N/A
	LIPE	ENST00000599918.2	TSL:5	c.3227_3245dupTAGACGGGGGCTGCGGGGG	p.His1084ArgfsTer8	frameshift	Exon 10 of 10	ENSP00000472218.2

Frequencies

GnomAD3 genomes AF: 0.000152 AC: 23 AN: 151792 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000119 AC: 1 AN: 83980 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000150 AC: 199 AN: 1328328 Hom.: 2 Cov.: 30 AF XY: 0.000144 AC XY: 94 AN XY: 652608

African (AFR) AF: 0.0000718 AC: 2 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: 0.000143 AC: 10 AN: 69930

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: 0.000174 AC: 183 AN: 1050186

Other (OTH) AF: 0.0000725 AC: 4 AN: 55154

GnomAD4 genome AF: 0.000151 AC: 23 AN: 151900 Hom.: 0 Cov.: 30 AF XY: 0.000135 AC XY: 10 AN XY: 74192

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

African (AFR) AF: 0.000121 AC: 5 AN: 41422

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

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

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

South Asian (SAS) AF: 0.000419 AC: 2 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: 0.000206 AC: 14 AN: 67930

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000140263), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

LIPE-related familial partial lipodystrophy Uncertain:1

Mar 11, 2024

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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

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;