10-89222511-C-T

Variant names:

• chr10-89222511-C-T
• rs116928232
• NM_000235.4:c.894G>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PS3 PP3_Strong PP5_Very_Strong BS2_Supporting

The NM_000235.4(LIPA):​c.894G>A​(p.Gln298Gln) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00111 in 1,603,504 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000238401: The variant has been shown to result in a major non-functional transcript (with skipping of exon 8), and a minor normally spliced protein with 5-10% residual enzyme activity (Kilma et al. 1993, PMID:8254026" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: LIPA NM_000235.4 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:33 O:2
• Conservation: PhyloP100: 7.08
• Publications: 78 publications found

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 Submitted by: ClinGen
• lysosomal acid lipase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• cholesteryl ester storage disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Wolman disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000238401: The variant has been shown to result in a major non-functional transcript (with skipping of exon 8), and a minor normally spliced protein with 5-10% residual enzyme activity (Kilma et al. 1993, PMID: 8254026; Fasano et al. 2012, PMID: 22227072).; SCV000898796: Of note, this variant is a silent variant and does not change the amino acid; however, functional studies suggest that this variant disrupts the normal splicing sequence, resulting in the alternate splicing and skipping of exon 8 (Pisciotta 2009 PMID:19307143, Fasano 2012 PMID:22227072, Bernstein 2013 PMID:23485521, Hoffman 2016 PMID:26225414).; SCV001193778: Functional assessments of this variant are available in the literature (PMID: 22227072, 21757691, 10562460).; SCV005622668: Functional studies have demonstrated that this variant leads to skipping of exon 8 in 95% of mRNA transcripts and the recombinant mutant protein lacks functional activity (PS3_STRONG; PMIDs 7751811, 9684740).; SCV000568149: Published functional studies demonstrate abnormal splicing resulting in an in-frame skipping of exon 8, with 3-5% of mRNA being spliced correctly (Fasano et al., 2012);; SCV000914469: Expression analysis in patient fibroblasts found lysosomal acidic lipase (LAL) activity to be reduced to 2-16% of wild type (Klima et al. 1993; Ameis et al. 1995; Fasano et al. 2012). Transfection of the variant into COS-1 cells resulted in reduced cholesteryl esterase activity compared to controls (Anderson et al. 1999).; SCV004115067: RNA analysis has demonstrated that this variant causes exon skipping, resulting in an in-frame deletion of 72 nucleotides and a protein with 5-10% residual activity (Ameis et al. 1995. PubMed ID: 7751811; Fasano. 2012. PubMed ID: 22227072).; SCV006583869: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 7759067, 8617513, 9684740).; SCV000819258: Experimental studies have shown that this variant affects LIPA function (PMID: 7759067, 8617513, 9684740).; SCV002556229: Multiple publications report experimental evidence that this variant disrupts the normal splicing sequence, resulting in alternate splicing and the skipping of exon 8 (e.g. Aslandis_1996, Pagani_1998).; SCV005042764: Experimental studies have shown that this variant affects LIPA function Pagani et al., 1998.; SCV002683966: Functional studies have demonstrated that this alteration causes in-frame skipping of exon 7, with only ~3% of mRNA spliced correctly (Klima H et al. J. Clin. Invest., 1993 Dec;92:2713-8; Ameis D et al. J. Lipid Res., 1995 Feb;36:241-50; Aslanidis C et al. Genomics, 1996 Apr;33:85-93; Fasano T et al. Mol. Genet. Metab., 2012 Mar;105:450-6).
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 10-89222511-C-T is Pathogenic according to our data. Variant chr10-89222511-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 203361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000235.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPA	NM_000235.4	MANE Select	c.894G>A	p.Gln298Gln	splice_region synonymous	Exon 8 of 10	NP_000226.2	P38571-1
	LIPA	NM_001440836.1		c.1026G>A	p.Gln342Gln	splice_region synonymous	Exon 9 of 11	NP_001427765.1
	LIPA	NM_001440837.1		c.915G>A	p.Gln305Gln	splice_region synonymous	Exon 8 of 10	NP_001427766.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPA	ENST00000336233.10	TSL:1 MANE Select	c.894G>A	p.Gln298Gln	splice_region synonymous	Exon 8 of 10	ENSP00000337354.5	P38571-1
	LIPA	ENST00000868683.1		c.915G>A	p.Gln305Gln	splice_region synonymous	Exon 8 of 10	ENSP00000538742.1
	LIPA	ENST00000938134.1		c.915G>A	p.Gln305Gln	splice_region synonymous	Exon 8 of 10	ENSP00000608193.1

Frequencies

GnomAD3 genomes AF: 0.000762 AC: 116 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000908 AC: 228 AN: 251194 AF XY: 0.000921

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00115 AC: 1666 AN: 1451190 Hom.: 2 Cov.: 28 AF XY: 0.00115 AC XY: 832 AN XY: 722786

African (AFR) AF: 0.000151 AC: 5 AN: 33218

American (AMR) AF: 0.00107 AC: 48 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 15 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.000546 AC: 47 AN: 86048

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00134 AC: 1478 AN: 1102322

Other (OTH) AF: 0.00107 AC: 64 AN: 60028

GnomAD4 genome AF: 0.000762 AC: 116 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000833 AC XY: 62 AN XY: 74470

African (AFR) AF: 0.000192 AC: 8 AN: 41582

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00153 AC: 104 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.000737

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
11	-	-	Lysosomal acid lipase deficiency (12)
8	-	-	not provided (8)
5	-	-	Cholesteryl ester storage disease (5)
3	-	-	LIPA-related disorder (3)
3	-	-	Wolman disease (4)
2	-	-	Cholesteryl ester storage disease;C0043208:Wolman disease (2)
1	-	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Uncertain	0.99
PhyloP100		7.1
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.91		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs116928232; hg19: chr10-90982268;