rs776472526

Positions:

• chr10-89215004-C-A
• chr10-89215004-C-G
• chr10-89215004-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000235.4(LIPA):​c.1024G>T​(p.Gly342Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LIPA NM_000235.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.99

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 10-89215004-C-A is Pathogenic according to our data. Variant chr10-89215004-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 695041.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIPA	NM_000235.4	c.1024G>T	p.Gly342Trp	missense_variant	10/10	ENST00000336233.10	NP_000226.2
LIPA	NM_001127605.3	c.1024G>T	p.Gly342Trp	missense_variant	10/10		NP_001121077.1
LIPA	NM_001288979.2	c.676G>T	p.Gly226Trp	missense_variant	8/8		NP_001275908.1
LIPA	XM_024448023.2	c.1024G>T	p.Gly342Trp	missense_variant	10/10		XP_024303791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIPA	ENST00000336233.10	c.1024G>T	p.Gly342Trp	missense_variant	10/10	1	NM_000235.4	ENSP00000337354	P1
LIPA	ENST00000371837.5	c.856G>T	p.Gly286Trp	missense_variant	9/9	2		ENSP00000360903
LIPA	ENST00000456827.5	c.676G>T	p.Gly226Trp	missense_variant	8/8	3		ENSP00000413019

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lysosomal acid lipase deficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Alexion Pharmaceuticals, Inc

Jun 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;.;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.5	H;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-7.5	D;D;.
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.96
MutPred		0.97		Loss of glycosylation at S341 (P = 0.0408);.;.;
MVP		0.92
MPC		0.68
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.94
gMVP		0.97

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: rs776472526; hg19: chr10-90974761;