rs1554865206

Positions:

• chr10-89222513-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000235.4(LIPA):​c.892C>T​(p.Gln298*) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q298Q) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LIPA NM_000235.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9982
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.93

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 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 10-89222513-G-A is Pathogenic according to our data. Variant chr10-89222513-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556586.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.892C>T	p.Gln298*	stop_gained, splice_region_variant	8/10	ENST00000336233.10	NP_000226.2
LIPA	NM_001127605.3	c.892C>T	p.Gln298*	stop_gained, splice_region_variant	8/10		NP_001121077.1
LIPA	NM_001288979.2	c.544C>T	p.Gln182*	stop_gained, splice_region_variant	6/8		NP_001275908.1
LIPA	XM_024448023.2	c.892C>T	p.Gln298*	stop_gained, splice_region_variant	8/10		XP_024303791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIPA	ENST00000336233.10	c.892C>T	p.Gln298*	stop_gained, splice_region_variant	8/10	1	NM_000235.4	ENSP00000337354.5
LIPA	ENST00000371837.5	c.724C>T	p.Gln242*	stop_gained, splice_region_variant	7/9	2		ENSP00000360903.1
LIPA	ENST00000456827.5	c.544C>T	p.Gln182*	stop_gained, splice_region_variant	6/8	3		ENSP00000413019.2
LIPA	ENST00000428800.5	c.*20C>T		downstream_gene_variant		1		ENSP00000388415.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451112 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 722698

Gnomad4 AFR exome AF: 0.0000301

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wolman disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2024

This sequence change creates a premature translational stop signal (p.Gln298*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Wolman disease (PMID: 8864960). This variant is also known as p.Gln277*. ClinVar contains an entry for this variant (Variation ID: 556586). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Lysosomal acid lipase deficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Feb 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	51
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.95
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.56		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554865206; hg19: chr10-90982270;