NM_000235.4:c.1070T>G

Variant names:

• chr10-89214958-A-C
• NM_000235.4:c.1070T>G

Variant summary

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

The NM_000235.4(LIPA):​c.1070T>G​(p.Leu357Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LIPA NM_000235.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.22

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPA	NM_000235.4	c.1070T>G	p.Leu357Arg	missense_variant	Exon 10 of 10	ENST00000336233.10	NP_000226.2
LIPA	NM_001127605.3	c.1070T>G	p.Leu357Arg	missense_variant	Exon 10 of 10		NP_001121077.1
LIPA	NM_001288979.2	c.722T>G	p.Leu241Arg	missense_variant	Exon 8 of 8		NP_001275908.1
LIPA	XM_024448023.2	c.1070T>G	p.Leu357Arg	missense_variant	Exon 10 of 10		XP_024303791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIPA	ENST00000336233.10	c.1070T>G	p.Leu357Arg	missense_variant	Exon 10 of 10	1	NM_000235.4	ENSP00000337354.5
LIPA	ENST00000371837.5	c.902T>G	p.Leu301Arg	missense_variant	Exon 9 of 9	2		ENSP00000360903.1
LIPA	ENST00000456827.5	c.722T>G	p.Leu241Arg	missense_variant	Exon 8 of 8	3		ENSP00000413019.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;.;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.63	D;D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.2	M;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.2	D;D;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.017	D;D;.
Sift4G	Uncertain	0.049	D;T;D
Polyphen		0.68	P;D;.
Vest4		0.54
MutPred		0.69		Loss of stability (P = 0.0739);.;.;
MVP		0.92
MPC		0.37
ClinPred		0.98	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-90974715;