chr10-89228249-G-A

Position:

chr10-89228249-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000235.4(LIPA):c.379C>T(p.Arg127Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,613,980 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

LIPA
NM_000235.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4

Conservation

PhyloP100: 1.51

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 Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.846

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LIPA	NM_000235.4 linkuse as main transcript	c.379C>T	p.Arg127Trp	missense_variant	4/10	ENST00000336233.10	NP_000226.2
LIPA	NM_001127605.3 linkuse as main transcript	c.379C>T	p.Arg127Trp	missense_variant	4/10		NP_001121077.1
LIPA	NM_001288979.2 linkuse as main transcript	c.31C>T	p.Arg11Trp	missense_variant	2/8		NP_001275908.1
LIPA	XM_024448023.2 linkuse as main transcript	c.379C>T	p.Arg127Trp	missense_variant	4/10		XP_024303791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIPA	ENST00000336233.10 linkuse as main transcript	c.379C>T	p.Arg127Trp	missense_variant	4/10	1	NM_000235.4	ENSP00000337354	P1	P38571-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251444

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000561

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000621

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.000121

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000761

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lysosomal acid lipase deficiency

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 08, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Feb 11, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Wolman disease

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 09, 2024	Variant summary: LIPA c.379C>T (p.Arg127Trp) results in a non-conservative amino acid change located in the Alpha/beta hydrolase fold-1 domain (IPR000073) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251444 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LIPA causing Lysosomal Acid Lipase Deficiency (4.8e-05 vs 0.0027), allowing no conclusion about variant significance. c.379C>T has been reported in the literature as a heterozygous genotype in at least one individual affected with Hypercholesterolemia (Vinje_2018). This report does not provide unequivocal conclusions about association of the variant with Lysosomal Acid Lipase Deficiency. Two publications reports experimental evidence evaluating an impact on enzymatic activity (Vinje_2018 and DelAngel_2019). The most pronounced variant effect results in <10% of normal Lysosomal acidic lipase activity. The following publications have been ascertained in the context of this evaluation (PMID: 29196158, 31131398, 31180157). ClinVar contains an entry for this variant (Variation ID: 528226). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 127 of the LIPA protein (p.Arg127Trp). This variant is present in population databases (rs140686447, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with LIPA-related conditions. ClinVar contains an entry for this variant (Variation ID: 528226). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LIPA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects LIPA function (PMID: 29196158, 31180157). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.00053

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.47

T;.;T;.;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.95

D;D;D;D;D

M_CAP

Benign

0.026

MetaRNN

Pathogenic

0.85

D;D;D;D;D

MetaSVM

Uncertain

0.32

MutationAssessor

Pathogenic

4.4

H;.;.;.;.

MutationTaster

Benign

0.97

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-6.3

D;D;.;D;D

REVEL

Uncertain

0.43

Sift

Uncertain

0.0010

D;D;.;D;D

Sift4G

Uncertain

0.022

D;D;D;.;.

Polyphen

1.0

D;D;.;.;.

Vest4

0.69

MVP

0.94

MPC

0.29

ClinPred

0.99

GERP RS

4.3

Varity_R

0.76

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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