rs1051339

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.67G>A(p.Gly23Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,612,192 control chromosomes in the GnomAD database, including 9,505 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. G23G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.13 ( 1590 hom., cov: 30)

Exomes 𝑓: 0.10 ( 7915 hom. )

Consequence

LIPA
NM_000235.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.386

Publications

23 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=0.0035889745).

BP6

Variant 10-89247582-C-T is Benign according to our data. Variant chr10-89247582-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPA	NM_000235.4 link	c.67G>A	p.Gly23Arg	missense_variant	Exon 2 of 10	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.67G>A	p.Gly23Arg	missense_variant	Exon 2 of 10	1	NM_000235.4	ENSP00000337354.5		P38571-1

Frequencies

GnomAD3 genomes

AF:

0.130

AC:

19710

AN:

151678

Hom.:

1588

Cov.:

show subpopulations

Gnomad AFR

AF:

0.222

Gnomad AMI

AF:

0.208

Gnomad AMR

AF:

0.101

Gnomad ASJ

AF:

0.0916

Gnomad EAS

AF:

0.0576

Gnomad SAS

AF:

0.0573

Gnomad FIN

AF:

0.0521

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.104

Gnomad OTH

AF:

0.124

GnomAD2 exomes

AF:

0.0948

AC:

23828

AN:

251382

AF XY:

0.0916

show subpopulations

Gnomad AFR exome

AF:

0.226

Gnomad AMR exome

AF:

0.0742

Gnomad ASJ exome

AF:

0.104

Gnomad EAS exome

AF:

0.0553

Gnomad FIN exome

AF:

0.0521

Gnomad NFE exome

AF:

0.104

Gnomad OTH exome

AF:

0.114

GnomAD4 exome

AF:

0.100

AC:

146658

AN:

1460396

Hom.:

7915

Cov.:

AF XY:

0.0989

AC XY:

71849

AN XY:

726598

show subpopulations

African (AFR)

AF:

0.221

AC:

7381

AN:

33422

American (AMR)

AF:

0.0770

AC:

3442

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0978

AC:

2555

AN:

26120

East Asian (EAS)

AF:

0.0594

AC:

2357

AN:

39688

South Asian (SAS)

AF:

0.0607

AC:

5235

AN:

86230

European-Finnish (FIN)

AF:

0.0552

AC:

2947

AN:

53406

Middle Eastern (MID)

AF:

0.110

AC:

634

AN:

5768

European-Non Finnish (NFE)

AF:

0.104

AC:

115659

AN:

1110712

Other (OTH)

AF:

0.107

AC:

6448

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

5879

11758

17638

23517

29396

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4214

8428

12642

16856

21070

<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:

0.130

AC:

19722

AN:

151796

Hom.:

1590

Cov.:

AF XY:

0.125

AC XY:

9250

AN XY:

74200

show subpopulations

African (AFR)

AF:

0.222

AC:

9198

AN:

41368

American (AMR)

AF:

0.101

AC:

1536

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.0916

AC:

318

AN:

3470

East Asian (EAS)

AF:

0.0576

AC:

297

AN:

5160

South Asian (SAS)

AF:

0.0567

AC:

273

AN:

4812

European-Finnish (FIN)

AF:

0.0521

AC:

547

AN:

10494

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.104

AC:

7068

AN:

67936

Other (OTH)

AF:

0.123

AC:

258

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

815

1630

2444

3259

4074

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

210

420

630

840

1050

<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:

0.114

Hom.:

4325

Bravo

AF:

0.140

TwinsUK

AF:

0.102

AC:

380

ALSPAC

AF:

0.103

AC:

396

ESP6500AA

AF:

0.226

AC:

997

ESP6500EA

AF:

0.106

AC:

912

ExAC

AF:

0.101

AC:

12225

Asia WGS

AF:

0.0660

AC:

230

AN:

3478

EpiCase

AF:

0.108

EpiControl

AF:

0.111

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

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

- -

Nov 21, 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. -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Dec 15, 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: 31182375) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

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

- -

PreventionGenetics, part of Exact Sciences

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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Feb 11, 2019

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

0.074

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

0.28

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.072

T;.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0015

LIST_S2

Benign

0.22

T;T;T

MetaRNN

Benign

0.0036

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;.;.

PhyloP100

-0.39

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.11

N;N;N

REVEL

Benign

0.13

Sift

Benign

0.59

T;T;T

Sift4G

Benign

0.58

T;.;.

Polyphen

0.0

B;.;.

Vest4

0.035

MutPred

0.12

Loss of glycosylation at S22 (P = 0.0317);Loss of glycosylation at S22 (P = 0.0317);Loss of glycosylation at S22 (P = 0.0317);

MPC

0.17

ClinPred

0.000031

GERP RS

-4.1

PromoterAI

0.0048

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.031

gMVP

0.43

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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