rs1051339

chr10-89247582-C-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.67G>A(p.Gly23Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,612,192 control chromosomes in the GnomAD database, including 9,505 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G23G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.13 (1590 hom., cov: 30)
  • Exomes 𝑓: 0.10 (7915 hom.)
• Consequence: LIPA NM_000235.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.386

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 (MetaRNN=0.0035889745).
• BP6: Variant 10-89247582-C-T is Benign according to our data. Variant chr10-89247582-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 255612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-89247582-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIPA	NM_000235.4	c.67G>A	p.Gly23Arg	missense_variant	2/10	ENST00000336233.10
LIPA	NM_001127605.3	c.67G>A	p.Gly23Arg	missense_variant	2/10
LIPA	XM_024448023.2	c.67G>A	p.Gly23Arg	missense_variant	2/10
LIPA	NM_001288979.2	c.-120+4155G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIPA	ENST00000336233.10	c.67G>A	p.Gly23Arg	missense_variant	2/10	1	NM_000235.4	P1

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19710 AN: 151678 Hom.: 1588 Cov.: 30

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.0916

Gnomad EAS AF: 0.0576

Gnomad SAS AF: 0.0573

Gnomad FIN AF: 0.0521

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.124

GnomAD3 exomes AF: 0.0948 AC: 23828 AN: 251382 Hom.: 1432 AF XY: 0.0916 AC XY: 12450 AN XY: 135866

Gnomad AFR exome AF: 0.226

Gnomad AMR exome AF: 0.0742

Gnomad ASJ exome AF: 0.104

Gnomad EAS exome AF: 0.0553

Gnomad SAS exome AF: 0.0623

Gnomad FIN exome AF: 0.0521

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.100 AC: 146658 AN: 1460396 Hom.: 7915 Cov.: 30 AF XY: 0.0989 AC XY: 71849 AN XY: 726598

Gnomad4 AFR exome AF: 0.221

Gnomad4 AMR exome AF: 0.0770

Gnomad4 ASJ exome AF: 0.0978

Gnomad4 EAS exome AF: 0.0594

Gnomad4 SAS exome AF: 0.0607

Gnomad4 FIN exome AF: 0.0552

Gnomad4 NFE exome AF: 0.104

Gnomad4 OTH exome AF: 0.107

GnomAD4 genome AF: 0.130 AC: 19722 AN: 151796 Hom.: 1590 Cov.: 30 AF XY: 0.125 AC XY: 9250 AN XY: 74200

Gnomad4 AFR AF: 0.222

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.0916

Gnomad4 EAS AF: 0.0576

Gnomad4 SAS AF: 0.0567

Gnomad4 FIN AF: 0.0521

Gnomad4 NFE AF: 0.104

Gnomad4 OTH AF: 0.123

Alfa AF: 0.110 Hom.: 1799

Bravo AF: 0.140

TwinsUK AF: 0.102 AC: 380

ALSPAC AF: 0.103 AC: 396

ESP6500AA AF: 0.226 AC: 997

ESP6500EA AF: 0.106 AC: 912

ExAC AF: 0.101 AC: 12225

Asia WGS AF: 0.0660 AC: 230 AN: 3478

EpiCase AF: 0.108

EpiControl AF: 0.111

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lysosomal acid lipase deficiency Benign:3

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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 21, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -

Wolman disease Benign:2

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 31182375) -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2015	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2019

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
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	0.28
Dann	Benign	0.49
DEOGEN2	Benign	0.072	T;.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.22	T;T;T
MetaRNN	Benign	0.0036	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.11	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.59	T;T;T
Sift4G	Benign	0.58	T;.;.
Polyphen		0.0	B;.;.
Vest4		0.035
MutPred		0.12		Loss of glycosylation at S22 (P = 0.0317);Loss of glycosylation at S22 (P = 0.0317);Loss of glycosylation at S22 (P = 0.0317);
MPC		0.17
ClinPred		0.000031	T
GERP RS		-4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.031
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1051339; hg19: chr10-91007339; COSMIC: COSV51078800;