NM_000235.4:c.883C>T

Variant names:

• chr10-89222522-G-A
• rs1554865214
• NM_000235.4:c.883C>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000235.4(LIPA):​c.883C>T​(p.His295Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LIPA NM_000235.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.93

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 10-89222522-G-A is Pathogenic according to our data. Variant chr10-89222522-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPA	NM_000235.4	c.883C>T	p.His295Tyr	missense_variant	Exon 8 of 10	ENST00000336233.10	NP_000226.2
LIPA	NM_001127605.3	c.883C>T	p.His295Tyr	missense_variant	Exon 8 of 10		NP_001121077.1
LIPA	NM_001288979.2	c.535C>T	p.His179Tyr	missense_variant	Exon 6 of 8		NP_001275908.1
LIPA	XM_024448023.2	c.883C>T	p.His295Tyr	missense_variant	Exon 8 of 10		XP_024303791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIPA	ENST00000336233.10	c.883C>T	p.His295Tyr	missense_variant	Exon 8 of 10	1	NM_000235.4	ENSP00000337354.5
LIPA	ENST00000371837.5	c.715C>T	p.His239Tyr	missense_variant	Exon 7 of 9	2		ENSP00000360903.1
LIPA	ENST00000456827.5	c.535C>T	p.His179Tyr	missense_variant	Exon 6 of 8	3		ENSP00000413019.2
LIPA	ENST00000428800.5	c.*11C>T		downstream_gene_variant		1		ENSP00000388415.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1456348 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 724984

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cholesteryl ester storage disease;C0043208:Wolman disease Pathogenic:1

May 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Wolman disease Pathogenic:1

May 01, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LIPA c.883C>T (p.His295Tyr) results in a conservative amino acid change in the Alpha/beta hydrolase fold-1 domain (IPR000073) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251260 control chromosomes. c.883C>T has been reported in the literature in individuals affected with cholesteryl ester storage disease (Fasano_2012). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in little secretion of LIPA into the culturing medium in HepG2 cells (Vinje_2019). The following publications have been ascertained in the context of this evaluation (PMID: 22227072, 31131398). ClinVar contains an entry for this variant (Variation ID: 556192). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Lysosomal acid lipase deficiency Pathogenic:1

Jan 17, 2018

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Pathogenic	4.3	H;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.7	D;D;.
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.98
MutPred		0.97		Loss of disorder (P = 0.0419);.;.;
MVP		0.96
MPC		0.67
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1554865214; hg19: chr10-90982279;