rs13500

Positions:

• chr10-89213735-G-A

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.*1093C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 152,176 control chromosomes in the GnomAD database, including 1,130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1130 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LIPA NM_000235.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.04

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=-0.87).
• BP6: Variant 10-89213735-G-A is Benign according to our data. Variant chr10-89213735-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 301549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIPA	NM_000235.4	c.*1093C>T		3_prime_UTR_variant	10/10	ENST00000336233.10	NP_000226.2
LIPA	NM_001127605.3	c.*1093C>T		3_prime_UTR_variant	10/10		NP_001121077.1
LIPA	NM_001288979.2	c.*1093C>T		3_prime_UTR_variant	8/8		NP_001275908.1
LIPA	XM_024448023.2	c.*1093C>T		3_prime_UTR_variant	10/10		XP_024303791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIPA	ENST00000336233.10	c.*1093C>T		3_prime_UTR_variant	10/10	1	NM_000235.4	ENSP00000337354	P1
LIPA	ENST00000371837.5	c.*1093C>T		3_prime_UTR_variant	9/9	2		ENSP00000360903
LIPA	ENST00000456827.5	c.*1093C>T		3_prime_UTR_variant	8/8	3		ENSP00000413019

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16788 AN: 152058 Hom.: 1128 Cov.: 32

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.0756

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.0891

Gnomad FIN AF: 0.0362

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.0996

Gnomad OTH AF: 0.115

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 10 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 8

Gnomad4 EAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.110 AC: 16803 AN: 152176 Hom.: 1130 Cov.: 32 AF XY: 0.107 AC XY: 7926 AN XY: 74414

Gnomad4 AFR AF: 0.172

Gnomad4 AMR AF: 0.0755

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.000963

Gnomad4 SAS AF: 0.0898

Gnomad4 FIN AF: 0.0362

Gnomad4 NFE AF: 0.0997

Gnomad4 OTH AF: 0.113

Alfa AF: 0.111 Hom.: 266

Bravo AF: 0.115

Asia WGS AF: 0.0520 AC: 182 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Wolman disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Lysosomal acid lipase deficiency Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.52
DANN	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs13500; hg19: chr10-90973492;