rs201242614

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000235.4(LIPA):c.966+3A>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,601,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

LIPA
NM_000235.4 splice_donor_region, intron

Scores

Splicing: ADA: 0.9991

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 3.49

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
LIPA	NM_000235.4 linkuse as main transcript	c.966+3A>T	splice_donor_region_variant, intron_variant	ENST00000336233.10
LIPA	NM_001127605.3 linkuse as main transcript	c.966+3A>T	splice_donor_region_variant, intron_variant
LIPA	NM_001288979.2 linkuse as main transcript	c.618+3A>T	splice_donor_region_variant, intron_variant
LIPA	XM_024448023.2 linkuse as main transcript	c.966+3A>T	splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
LIPA	ENST00000336233.10 linkuse as main transcript	c.966+3A>T	splice_donor_region_variant, intron_variant	1	NM_000235.4	P1	P38571-1
LIPA	ENST00000371837.5 linkuse as main transcript	c.798+3A>T	splice_donor_region_variant, intron_variant	2			P38571-2
LIPA	ENST00000456827.5 linkuse as main transcript	c.618+3A>T	splice_donor_region_variant, intron_variant	3

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000151

AC:

AN:

251392

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000202

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000140

AC:

203

AN:

1449202

Hom.:

Cov.:

AF XY:

0.000139

AC XY:

100

AN XY:

721908

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000166

Gnomad4 OTH exome

AF:

0.0000833

GnomAD4 genome

AF:

0.000171

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000916

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000140

Hom.:

Bravo

AF:

0.000264

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lysosomal acid lipase deficiency

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 20, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 31, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 26, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 04, 2023

Variant summary: LIPA c.966+3A>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00015 in 251392 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in LIPA causing Lysosomal Acid Lipase Deficiency (0.00015 vs 0.0027), allowing no conclusion about variant significance. c.966+3A>T has been reported in the literature in an individual affected with familial hypercholesterolemia (example:Sjouke_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Lysosomal Acid Lipase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Wolman disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2022

This sequence change falls in intron 9 of the LIPA gene. It does not directly change the encoded amino acid sequence of the LIPA protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs201242614, gnomAD 0.03%). This variant has been observed in individual(s) with hypercholesterolemia (PMID: 27423329). ClinVar contains an entry for this variant (Variation ID: 499076). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.26

Cadd

Benign

Dann

Benign

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

SpliceAI score (max)

0.67

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.67

Position offset: 3

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