rs1554865576
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000235.4(LIPA):c.656T>G(p.Leu219Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L219L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
LIPA
NM_000235.4 stop_gained
NM_000235.4 stop_gained
Scores
2
2
3
Clinical Significance
Conservation
PhyloP100: 6.28
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 12 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 10-89225111-A-C is Pathogenic according to our data. Variant chr10-89225111-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 458507.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LIPA | NM_000235.4 | c.656T>G | p.Leu219Ter | stop_gained | 6/10 | ENST00000336233.10 | |
LIPA | NM_001127605.3 | c.656T>G | p.Leu219Ter | stop_gained | 6/10 | ||
LIPA | NM_001288979.2 | c.308T>G | p.Leu103Ter | stop_gained | 4/8 | ||
LIPA | XM_024448023.2 | c.656T>G | p.Leu219Ter | stop_gained | 6/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LIPA | ENST00000336233.10 | c.656T>G | p.Leu219Ter | stop_gained | 6/10 | 1 | NM_000235.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Wolman disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2021 | Loss-of-function variants in LIPA are known to be pathogenic (PMID: 23485521). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with LIPA-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu219*) in the LIPA gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A;A;A;D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at