rs762559980
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000235.4(LIPA):βc.482delβ(p.Asn161IlefsTer19) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000149 in 1,613,520 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000013 ( 0 hom., cov: 33)
Exomes π: 0.000015 ( 0 hom. )
Consequence
LIPA
NM_000235.4 frameshift
NM_000235.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.78
Genes affected
LIPA (HGNC:6617): (lipase A, lysosomal acid type) This gene encodes lipase A, the lysosomal acid lipase (also known as cholesterol ester hydrolase). This enzyme functions in the lysosome to catalyze the hydrolysis of cholesteryl esters and triglycerides. Mutations in this gene can result in Wolman disease and cholesteryl ester storage disease. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 10-89226950-AT-A is Pathogenic according to our data. Variant chr10-89226950-AT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 552285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LIPA | NM_000235.4 | c.482del | p.Asn161IlefsTer19 | frameshift_variant | 5/10 | ENST00000336233.10 | NP_000226.2 | |
LIPA | NM_001127605.3 | c.482del | p.Asn161IlefsTer19 | frameshift_variant | 5/10 | NP_001121077.1 | ||
LIPA | NM_001288979.2 | c.134del | p.Asn45IlefsTer19 | frameshift_variant | 3/8 | NP_001275908.1 | ||
LIPA | XM_024448023.2 | c.482del | p.Asn161IlefsTer19 | frameshift_variant | 5/10 | XP_024303791.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LIPA | ENST00000336233.10 | c.482del | p.Asn161IlefsTer19 | frameshift_variant | 5/10 | 1 | NM_000235.4 | ENSP00000337354 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152242Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251412Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135872
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GnomAD4 exome AF: 0.0000151 AC: 22AN: 1461278Hom.: 0 Cov.: 29 AF XY: 0.0000165 AC XY: 12AN XY: 726978
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152242Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74374
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Wolman disease Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 09, 2023 | This premature translational stop signal has been observed in individual(s) with Wolman disease (PMID: 21963785). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs762559980, gnomAD 0.008%). This sequence change creates a premature translational stop signal (p.Asn161Ilefs*19) in the LIPA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LIPA are known to be pathogenic (PMID: 23485521). ClinVar contains an entry for this variant (Variation ID: 552285). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 13, 2024 | Variant summary: LIPA c.482delA (p.Asn161IlefsX19) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 2.4e-05 in 251412 control chromosomes. c.482delA has been reported in the literature in at-least one individual affected with Wolman disease (example, Lee_2011). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 21963785). ClinVar contains an entry for this variant (Variation ID: 552285). Based on the evidence outlined above, the variant was classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2011 | - - |
Lysosomal acid lipase deficiency Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 17, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 02, 2017 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at