NM_000235.4:c.676-2A>G

Variant names:

• chr10-89223832-T-C
• rs747508159
• NM_000235.4:c.676-2A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000235.4(LIPA):​c.676-2A>G variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LIPA NM_000235.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.11

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.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.1225 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5, offset of 33, new splice context is: acaaagaatttcttccccAGagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-89223832-T-C is Pathogenic according to our data. Variant chr10-89223832-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 554255.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPA	NM_000235.4	c.676-2A>G		splice_acceptor_variant, intron_variant	Intron 6 of 9	ENST00000336233.10	NP_000226.2
LIPA	NM_001127605.3	c.676-2A>G		splice_acceptor_variant, intron_variant	Intron 6 of 9		NP_001121077.1
LIPA	NM_001288979.2	c.328-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 7		NP_001275908.1
LIPA	XM_024448023.2	c.676-2A>G		splice_acceptor_variant, intron_variant	Intron 6 of 9		XP_024303791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIPA	ENST00000336233.10	c.676-2A>G		splice_acceptor_variant, intron_variant	Intron 6 of 9	1	NM_000235.4	ENSP00000337354.5
LIPA	ENST00000428800.5	c.676-2A>G		splice_acceptor_variant, intron_variant	Intron 5 of 6	1		ENSP00000388415.1
LIPA	ENST00000371837.5	c.508-2A>G		splice_acceptor_variant, intron_variant	Intron 5 of 8	2		ENSP00000360903.1
LIPA	ENST00000456827.5	c.328-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 7	3		ENSP00000413019.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lysosomal acid lipase deficiency Pathogenic:1

Oct 12, 2017

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
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
GERP RS		4.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.81		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs747508159; hg19: chr10-90983589;