10-89247603-T-A

Position:

• chr10-89247603-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000235.4(LIPA):​c.46A>T​(p.Thr16Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T16P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 29)
• Consequence: LIPA NM_000235.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00200

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13717353).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIPA	NM_000235.4	c.46A>T	p.Thr16Ser	missense_variant	2/10	ENST00000336233.10
LIPA	NM_001127605.3	c.46A>T	p.Thr16Ser	missense_variant	2/10
LIPA	XM_024448023.2	c.46A>T	p.Thr16Ser	missense_variant	2/10
LIPA	NM_001288979.2	c.-120+4134A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIPA	ENST00000336233.10	c.46A>T	p.Thr16Ser	missense_variant	2/10	1	NM_000235.4	P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	5.4
DANN	Benign	0.55
DEOGEN2	Benign	0.053	T;.;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.38	T;T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.17	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.55	T;T;T
Sift4G	Benign	0.37	T;.;.
Polyphen		0.013	B;.;.
Vest4		0.072
MutPred		0.42		Gain of disorder (P = 0.0466);Gain of disorder (P = 0.0466);Gain of disorder (P = 0.0466);
MVP		0.83
MPC		0.14
ClinPred		0.067	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.050
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1051338; hg19: chr10-91007360;