rs2297472

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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

Publications

25 publications found

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 Gene-Disease associations (from GenCC):

lysosomal acid lipase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
cholesteryl ester storage disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Wolman disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LIPA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 255610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	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

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

GnomAD2 exomes

AF:

0.289

AC:

72636

AN:

251068

AF XY:

0.282

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 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

African (AFR)

AF:

0.0998

AC:

3341

AN:

33466

American (AMR)

AF:

0.453

AC:

20255

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.234

AC:

6116

AN:

26130

East Asian (EAS)

AF:

0.729

AC:

28921

AN:

39692

South Asian (SAS)

AF:

0.315

AC:

27139

AN:

86236

European-Finnish (FIN)

AF:

0.259

AC:

13811

AN:

53404

Middle Eastern (MID)

AF:

0.264

AC:

1524

AN:

5768

European-Non Finnish (NFE)

AF:

0.185

AC:

206116

AN:

1111180

Other (OTH)

AF:

0.237

AC:

14288

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

12339

24678

37016

49355

61694

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7570

15140

22710

30280

37850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.209

AC:

31753

AN:

152124

Hom.:

4540

Cov.:

AF XY:

0.218

AC XY:

16200

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.106

AC:

4393

AN:

41500

American (AMR)

AF:

0.321

AC:

4913

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.237

AC:

823

AN:

3472

East Asian (EAS)

AF:

0.729

AC:

3767

AN:

5168

South Asian (SAS)

AF:

0.327

AC:

1574

AN:

4820

European-Finnish (FIN)

AF:

0.255

AC:

2694

AN:

10558

Middle Eastern (MID)

AF:

0.298

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.189

AC:

12829

AN:

67998

Other (OTH)

AF:

0.222

AC:

468

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1170

2340

3509

4679

5849

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

346

692

1038

1384

1730

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.195

Hom.:

10778

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 06, 2022

GENinCode PLC

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 20, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

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. -

not provided

Benign:3

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

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

DANN

Benign

0.85

PhyloP100

0.22

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over