rs2297472

chr10-89225233-G-Achr10-89225233-G-Cchr10-89225233-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000235.4(LIPA):c.539-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,613,070 control chromosomes in the GnomAD database, including 48,404 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4540 hom., cov: 32)
  • Exomes 𝑓: 0.22 (43864 hom.)
• Consequence: LIPA NM_000235.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003292
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.224

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 10-89225233-G-A is Benign according to our data. Variant chr10-89225233-G-A is described in ClinVar as [Benign]. Clinvar id is 255610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-89225233-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIPA	NM_000235.4	c.539-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000336233.10
LIPA	NM_001127605.3	c.539-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
LIPA	NM_001288979.2	c.191-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
LIPA	XM_024448023.2	c.539-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIPA	ENST00000336233.10	c.539-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000235.4	P1

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31723 AN: 152006 Hom.: 4533 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.729

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.221

GnomAD3 exomes AF: 0.289 AC: 72636 AN: 251068 Hom.: 14075 AF XY: 0.282 AC XY: 38316 AN XY: 135730

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.472

Gnomad ASJ exome AF: 0.237

Gnomad EAS exome AF: 0.738

Gnomad SAS exome AF: 0.315

Gnomad FIN exome AF: 0.261

Gnomad NFE exome AF: 0.193

Gnomad OTH exome AF: 0.263

GnomAD4 exome AF: 0.220 AC: 321511 AN: 1460946 Hom.: 43864 Cov.: 34 AF XY: 0.222 AC XY: 161564 AN XY: 726822

Gnomad4 AFR exome AF: 0.0998

Gnomad4 AMR exome AF: 0.453

Gnomad4 ASJ exome AF: 0.234

Gnomad4 EAS exome AF: 0.729

Gnomad4 SAS exome AF: 0.315

Gnomad4 FIN exome AF: 0.259

Gnomad4 NFE exome AF: 0.185

Gnomad4 OTH exome AF: 0.237

GnomAD4 genome AF: 0.209 AC: 31753 AN: 152124 Hom.: 4540 Cov.: 32 AF XY: 0.218 AC XY: 16200 AN XY: 74358

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.321

Gnomad4 ASJ AF: 0.237

Gnomad4 EAS AF: 0.729

Gnomad4 SAS AF: 0.327

Gnomad4 FIN AF: 0.255

Gnomad4 NFE AF: 0.189

Gnomad4 OTH AF: 0.222

Alfa AF: 0.189 Hom.: 4972

Bravo AF: 0.215

Asia WGS AF: 0.471 AC: 1634 AN: 3478

EpiCase AF: 0.195

EpiControl AF: 0.188

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lysosomal acid lipase deficiency Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Wolman disease Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 26, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2018

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
BayesDel_noAF	Benign	-0.68
Cadd	Benign	6.6
Dann	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs2297472; hg19: chr10-90984990; COSMIC: COSV51079077;