NM_000235.4:c.796G>T

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.796G>T(p.Gly266*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000806 in 1,612,760 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: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

LIPA
NM_000235.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 5.33

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 10-89223710-C-A is Pathogenic according to our data. Variant chr10-89223710-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 78.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-89223710-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPA	NM_000235.4 link	c.796G>T	p.Gly266*	stop_gained	Exon 7 of 10	ENST00000336233.10	NP_000226.2	P38571-1
LIPA	NM_001127605.3 link	c.796G>T	p.Gly266*	stop_gained	Exon 7 of 10		NP_001121077.1	P38571-1
LIPA	NM_001288979.2 link	c.448G>T	p.Gly150*	stop_gained	Exon 5 of 8		NP_001275908.1	P38571A0A0A0MT32
LIPA	XM_024448023.2 link	c.796G>T	p.Gly266*	stop_gained	Exon 7 of 10		XP_024303791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LIPA	ENST00000336233.10 link	c.796G>T	p.Gly266*	stop_gained	Exon 7 of 10	1	NM_000235.4	ENSP00000337354.5	P38571-1
LIPA	ENST00000428800.5 link	c.796G>T	p.Gly266*	stop_gained	Exon 6 of 7	1		ENSP00000388415.1	Q5T073
LIPA	ENST00000371837.5 link	c.628G>T	p.Gly210*	stop_gained	Exon 6 of 9	2		ENSP00000360903.1	P38571-2
LIPA	ENST00000456827.5 link	c.448G>T	p.Gly150*	stop_gained	Exon 5 of 8	3		ENSP00000413019.2	A0A0A0MT32

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152040

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250494

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135620

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:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1460720

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726720

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:

0.00000720

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152040

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74248

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000526

Hom.:

Bravo

AF:

0.0000113

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lysosomal acid lipase deficiency

Pathogenic:2

May 28, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 22, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Jul 26, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies found this variant is associated with reduced lysosomal acid lipase activity (Vinje T et al., 2018); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 23928541, 28881270, 29196158, 26252914, 22227072, 30684275, 8617513, 33857477, 8254026) -

Jul 01, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cholesteryl ester storage disease;C0043208:Wolman disease

Pathogenic:1

Feb 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Wolman disease

Pathogenic:1

Oct 21, 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.Gly266*) 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 (rs267607218, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with lysosomal acid lipase (LAL) deficiency (PMID: 28881270, 30684275). ClinVar contains an entry for this variant (Variation ID: 78). 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. -

Cholesteryl ester storage disease

Pathogenic:1

Apr 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.98

Vest4

0.99

GERP RS

4.4

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.34

Position offset: -26

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