rs121965087
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000235.4(LIPA):c.129C>G(p.Tyr43Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,418,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
LIPA
NM_000235.4 stop_gained
NM_000235.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 2.30
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 10-89245776-G-C is Pathogenic according to our data. Variant chr10-89245776-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 82.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.129C>G | p.Tyr43Ter | stop_gained | 3/10 | ENST00000336233.10 | |
LIPA | NM_001127605.3 | c.129C>G | p.Tyr43Ter | stop_gained | 3/10 | ||
LIPA | XM_024448023.2 | c.129C>G | p.Tyr43Ter | stop_gained | 3/10 | ||
LIPA | NM_001288979.2 | c.-120+5961C>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LIPA | ENST00000336233.10 | c.129C>G | p.Tyr43Ter | stop_gained | 3/10 | 1 | NM_000235.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000141 AC: 2AN: 1418858Hom.: 0 Cov.: 25 AF XY: 0.00000141 AC XY: 1AN XY: 708602
GnomAD4 exome
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2
AN:
1418858
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Cov.:
25
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AC XY:
1
AN XY:
708602
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Wolman disease Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1996 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 29, 2019 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in LIPA are known to be pathogenic (PMID: 23485521). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been reported to affect LIPA protein function (PMID: 29196158). This variant has been observed in an individual affected with Wolman disease (PMID: 8956047). This variant is also known as p.Tyr22X in the literature. ClinVar contains an entry for this variant (Variation ID: 82). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr43*) 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
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A;A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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