rs770074196

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000235.4(LIPA):c.684delT(p.Phe228LeufsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,613,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

LIPA
NM_000235.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 3.01

Variant links:

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]

LIPA links:

Genome browser will be placed here

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 10-89223821-CA-C is Pathogenic according to our data. Variant chr10-89223821-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 553192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPA	NM_000235.4 link	c.684delT	p.Phe228LeufsTer13	frameshift_variant	Exon 7 of 10	ENST00000336233.10	NP_000226.2	P38571-1
LIPA	NM_001127605.3 link	c.684delT	p.Phe228LeufsTer13	frameshift_variant	Exon 7 of 10		NP_001121077.1	P38571-1
LIPA	NM_001288979.2 link	c.336delT	p.Phe112LeufsTer13	frameshift_variant	Exon 5 of 8		NP_001275908.1	P38571A0A0A0MT32
LIPA	XM_024448023.2 link	c.684delT	p.Phe228LeufsTer13	frameshift_variant	Exon 7 of 10		XP_024303791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LIPA	ENST00000336233.10 link	c.684delT	p.Phe228LeufsTer13	frameshift_variant	Exon 7 of 10	1	NM_000235.4	ENSP00000337354.5	P38571-1
LIPA	ENST00000428800.5 link	c.684delT	p.Phe228LeufsTer13	frameshift_variant	Exon 6 of 7	1		ENSP00000388415.1	Q5T073
LIPA	ENST00000371837.5 link	c.516delT	p.Phe172LeufsTer13	frameshift_variant	Exon 6 of 9	2		ENSP00000360903.1	P38571-2
LIPA	ENST00000456827.5 link	c.336delT	p.Phe112LeufsTer13	frameshift_variant	Exon 5 of 8	3		ENSP00000413019.2	A0A0A0MT32

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250966

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135752

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000472

AC:

AN:

1461802

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727208

show subpopulations

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:

0.0000612

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lysosomal acid lipase deficiency

Pathogenic:3

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 04, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 11, 2024

GENinCode PLC

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.684del p.(Phe228LeufsTer13) variant in LIPA is a frameshift variant that is predicted to undergo nonsense mediated decay in a gene where loss-of-function is an established disease mechanism (PVS1_VERY STRONG). This variant has been detected in multiple individuals with a clinical diagnosis of Lysosomal Acid Lipase Deficiency who also carried a second pathogenic/ likely pathogenic LIPA variant (PM3_STRONG, PP4_SUPPORTING; PMIDs 10562460, 10627498, 31412917, 34020687). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001763 in European (non-Finnish) population (PM2_MODERATE). Functional studies demonstrate impaired LAL enzyme activity (PS3_STRONG; PMIDs 10562460, 29196158, 31180157). Based on the evidence listed above, this variant has been classified as pathogenic. -

Wolman disease

Pathogenic:1

Mar 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Phe228Leufs*13) 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 present in population databases (rs770074196, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with cholesteryl ester storage disease (PMID: 10562460, 10627498). ClinVar contains an entry for this variant (Variation ID: 553192). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects LIPA function (PMID: 29196158). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over