NM_000235.4:c.539-5C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000235.4(LIPA):c.539-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,613,070 control chromosomes in the GnomAD database, including 48,404 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 4540 hom., cov: 32)

Exomes 𝑓: 0.22 ( 43864 hom. )

Consequence

LIPA
NM_000235.4 splice_region, intron

Scores

Splicing: ADA: 0.00003292

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.224

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 10-89225233-G-A is Benign according to our data. Variant chr10-89225233-G-A is described in ClinVar as [Benign]. Clinvar id is 255610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-89225233-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
LIPA	NM_000235.4 link	c.539-5C>T	splice_region_variant, intron_variant	Intron 5 of 9	ENST00000336233.10	NP_000226.2	P38571-1
LIPA	NM_001127605.3 link	c.539-5C>T	splice_region_variant, intron_variant	Intron 5 of 9		NP_001121077.1	P38571-1
LIPA	NM_001288979.2 link	c.191-5C>T	splice_region_variant, intron_variant	Intron 3 of 7		NP_001275908.1	P38571A0A0A0MT32
LIPA	XM_024448023.2 link	c.539-5C>T	splice_region_variant, intron_variant	Intron 5 of 9		XP_024303791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIPA	ENST00000336233.10 link	c.539-5C>T		splice_region_variant, intron_variant	Intron 5 of 9	1	NM_000235.4	ENSP00000337354.5		P38571-1

Frequencies

GnomAD3 genomes

AF:

0.209

AC:

31723

AN:

152006

Hom.:

4533

Cov.:

show subpopulations

Gnomad AFR

AF:

0.106

Gnomad AMI

AF:

0.225

Gnomad AMR

AF:

0.320

Gnomad ASJ

AF:

0.237

Gnomad EAS

AF:

0.729

Gnomad SAS

AF:

0.325

Gnomad FIN

AF:

0.255

Gnomad MID

AF:

0.306

Gnomad NFE

AF:

0.189

Gnomad OTH

AF:

0.221

GnomAD3 exomes

AF:

0.289

AC:

72636

AN:

251068

Hom.:

14075

AF XY:

0.282

AC XY:

38316

AN XY:

135730

show subpopulations

Gnomad AFR exome

AF:

0.101

Gnomad AMR exome

AF:

0.472

Gnomad ASJ exome

AF:

0.237

Gnomad EAS exome

AF:

0.738

Gnomad SAS exome

AF:

0.315

Gnomad FIN exome

AF:

0.261

Gnomad NFE exome

AF:

0.193

Gnomad OTH exome

AF:

0.263

GnomAD4 exome

AF:

0.220

AC:

321511

AN:

1460946

Hom.:

43864

Cov.:

AF XY:

0.222

AC XY:

161564

AN XY:

726822

show subpopulations

Gnomad4 AFR exome

AF:

0.0998

Gnomad4 AMR exome

AF:

0.453

Gnomad4 ASJ exome

AF:

0.234

Gnomad4 EAS exome

AF:

0.729

Gnomad4 SAS exome

AF:

0.315

Gnomad4 FIN exome

AF:

0.259

Gnomad4 NFE exome

AF:

0.185

Gnomad4 OTH exome

AF:

0.237

GnomAD4 genome

AF:

0.209

AC:

31753

AN:

152124

Hom.:

4540

Cov.:

AF XY:

0.218

AC XY:

16200

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.106

Gnomad4 AMR

AF:

0.321

Gnomad4 ASJ

AF:

0.237

Gnomad4 EAS

AF:

0.729

Gnomad4 SAS

AF:

0.327

Gnomad4 FIN

AF:

0.255

Gnomad4 NFE

AF:

0.189

Gnomad4 OTH

AF:

0.222

Alfa

AF:

0.189

Hom.:

4972

Bravo

AF:

0.215

Asia WGS

AF:

0.471

AC:

1634

AN:

3478

EpiCase

AF:

0.195

EpiControl

AF:

0.188

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lysosomal acid lipase deficiency

Benign:4

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 20, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 06, 2022

GENinCode PLC

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 26, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Wolman disease

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 11, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

6.6

DANN

Benign

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000033

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.0

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