10-89247603-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000235.4(LIPA):c.46A>C(p.Thr16Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 1,610,980 control chromosomes in the GnomAD database, including 77,838 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T16T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.26 ( 5848 hom., cov: 29)

Exomes 𝑓: 0.31 ( 71990 hom. )

Consequence

LIPA
NM_000235.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.00200

Publications

94 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 -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 39 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 0.22832 (below the threshold of 3.09). Trascript score misZ: 0.63421 (below the threshold of 3.09). GenCC associations: The gene is linked to cholesteryl ester storage disease, lysosomal acid lipase deficiency, Wolman disease.

BP4

Computational evidence support a benign effect (MetaRNN=0.0055990517).

BP6

Variant 10-89247603-T-G is Benign according to our data. Variant chr10-89247603-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPA	NM_000235.4 link	c.46A>C	p.Thr16Pro	missense_variant	Exon 2 of 10	ENST00000336233.10	NP_000226.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIPA	ENST00000336233.10 link	c.46A>C	p.Thr16Pro	missense_variant	Exon 2 of 10	1	NM_000235.4	ENSP00000337354.5

Frequencies

GnomAD3 genomes

AF:

0.262

AC:

39685

AN:

151432

Hom.:

5829

Cov.:

show subpopulations

Gnomad AFR

AF:

0.129

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.329

Gnomad ASJ

AF:

0.339

Gnomad EAS

AF:

0.318

Gnomad SAS

AF:

0.416

Gnomad FIN

AF:

0.334

Gnomad MID

AF:

0.358

Gnomad NFE

AF:

0.298

Gnomad OTH

AF:

0.271

GnomAD2 exomes

AF:

0.322

AC:

80785

AN:

251232

AF XY:

0.327

show subpopulations

Gnomad AFR exome

AF:

0.123

Gnomad AMR exome

AF:

0.389

Gnomad ASJ exome

AF:

0.324

Gnomad EAS exome

AF:

0.304

Gnomad FIN exome

AF:

0.342

Gnomad NFE exome

AF:

0.302

Gnomad OTH exome

AF:

0.322

GnomAD4 exome

AF:

0.309

AC:

451410

AN:

1459430

Hom.:

71990

Cov.:

AF XY:

0.313

AC XY:

227227

AN XY:

726138

show subpopulations

African (AFR)

AF:

0.123

AC:

4129

AN:

33464

American (AMR)

AF:

0.386

AC:

17274

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.331

AC:

8632

AN:

26118

East Asian (EAS)

AF:

0.262

AC:

10416

AN:

39688

South Asian (SAS)

AF:

0.415

AC:

35793

AN:

86188

European-Finnish (FIN)

AF:

0.349

AC:

18625

AN:

53406

Middle Eastern (MID)

AF:

0.343

AC:

1980

AN:

5768

European-Non Finnish (NFE)

AF:

0.302

AC:

335404

AN:

1109786

Other (OTH)

AF:

0.318

AC:

19157

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

15158

30316

45474

60632

75790

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11106

22212

33318

44424

55530

<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:

0.262

AC:

39730

AN:

151550

Hom.:

5848

Cov.:

AF XY:

0.264

AC XY:

19519

AN XY:

74022

show subpopulations

African (AFR)

AF:

0.130

AC:

5364

AN:

41352

American (AMR)

AF:

0.330

AC:

5018

AN:

15200

Ashkenazi Jewish (ASJ)

AF:

0.339

AC:

1177

AN:

3468

East Asian (EAS)

AF:

0.317

AC:

1633

AN:

5148

South Asian (SAS)

AF:

0.416

AC:

1993

AN:

4796

European-Finnish (FIN)

AF:

0.334

AC:

3482

AN:

10424

Middle Eastern (MID)

AF:

0.367

AC:

108

AN:

294

European-Non Finnish (NFE)

AF:

0.298

AC:

20245

AN:

67854

Other (OTH)

AF:

0.270

AC:

568

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

1430

2860

4291

5721

7151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

434

868

1302

1736

2170

<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:

0.287

Hom.:

20178

Bravo

AF:

0.254

TwinsUK

AF:

0.310

AC:

1148

ALSPAC

AF:

0.305

AC:

1174

ESP6500AA

AF:

0.129

AC:

568

ESP6500EA

AF:

0.298

AC:

2566

ExAC

AF:

0.316

AC:

38377

Asia WGS

AF:

0.379

AC:

1318

AN:

3478

EpiCase

AF:

0.303

EpiControl

AF:

0.302

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lysosomal acid lipase deficiency

Benign:5

Jul 06, 2022

GENinCode PLC

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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. -

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

- -

not specified

Benign:4

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 27, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22395809, 31645127, 29196158, 28279971) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely 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

- -

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

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;.;T

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.29

T;T;T

MetaRNN

Benign

0.0056

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;.;.

PhyloP100

0.0020

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.19

Sift

Benign

0.24

T;T;T

Sift4G

Benign

0.14

T;.;.

Polyphen

0.0020

B;.;.

Vest4

0.068

MPC

0.48

ClinPred

0.017

GERP RS

3.7

PromoterAI

0.00070

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.20

gMVP

0.56

Mutation Taster

=93/7

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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