rs1131706

chr10-89213919-A-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.*909T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 152,178 control chromosomes in the GnomAD database, including 4,601 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4601 hom., cov: 32)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: LIPA NM_000235.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.515

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=-0.78).
• BP6: Variant 10-89213919-A-T is Benign according to our data. Variant chr10-89213919-A-T is described in ClinVar as [Benign]. Clinvar id is 301555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.404 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIPA	NM_000235.4	c.*909T>A		3_prime_UTR_variant	10/10	ENST00000336233.10
LIPA	NM_001127605.3	c.*909T>A		3_prime_UTR_variant	10/10
LIPA	NM_001288979.2	c.*909T>A		3_prime_UTR_variant	8/8
LIPA	XM_024448023.2	c.*909T>A		3_prime_UTR_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIPA	ENST00000336233.10	c.*909T>A		3_prime_UTR_variant	10/10	1	NM_000235.4	P1
LIPA	ENST00000371837.5	c.*909T>A		3_prime_UTR_variant	9/9	2
LIPA	ENST00000456827.5	c.*909T>A		3_prime_UTR_variant	8/8	3

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31823 AN: 152058 Hom.: 4579 Cov.: 32

Gnomad AFR AF: 0.409

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.0588

Gnomad EAS AF: 0.0406

Gnomad SAS AF: 0.0993

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.177

GnomAD4 exome AF: 0.500 AC: 1 AN: 2 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

Gnomad4 NFE exome AF: 0.500

GnomAD4 genome AF: 0.209 AC: 31879 AN: 152176 Hom.: 4601 Cov.: 32 AF XY: 0.204 AC XY: 15185 AN XY: 74396

Gnomad4 AFR AF: 0.409

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.0588

Gnomad4 EAS AF: 0.0407

Gnomad4 SAS AF: 0.0975

Gnomad4 FIN AF: 0.134

Gnomad4 NFE AF: 0.150

Gnomad4 OTH AF: 0.177

Alfa AF: 0.181 Hom.: 418

Bravo AF: 0.217

Asia WGS AF: 0.118 AC: 415 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wolman disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2021

- -

Lysosomal acid lipase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.78
Cadd	Benign	6.5
Dann	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1131706; hg19: chr10-90973676;