rs121965087

Positions:

• chr10-89245776-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• 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]

ACMG classification

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	Protein	UniProt
LIPA	NM_000235.4	c.129C>G	p.Tyr43Ter	stop_gained	3/10	ENST00000336233.10	NP_000226.2
LIPA	NM_001127605.3	c.129C>G	p.Tyr43Ter	stop_gained	3/10		NP_001121077.1
LIPA	XM_024448023.2	c.129C>G	p.Tyr43Ter	stop_gained	3/10		XP_024303791.1
LIPA	NM_001288979.2	c.-120+5961C>G		intron_variant			NP_001275908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIPA	ENST00000336233.10	c.129C>G	p.Tyr43Ter	stop_gained	3/10	1	NM_000235.4	ENSP00000337354	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1418858 Hom.: 0 Cov.: 25 AF XY: 0.00000141 AC XY: 1 AN XY: 708602

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Wolman disease Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1996	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.78	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
Vest4		0.81
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121965087; hg19: chr10-91005533;