chr10-89223823-A-T

Variant names:

• chr10-89223823-A-T
• rs2228159
• NM_000235.4:c.683T>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_000235.4(LIPA):​c.683T>A​(p.Phe228Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. F228S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LIPA NM_000235.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.50

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-89223823-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPA	NM_000235.4	c.683T>A	p.Phe228Tyr	missense_variant	Exon 7 of 10	ENST00000336233.10	NP_000226.2
LIPA	NM_001127605.3	c.683T>A	p.Phe228Tyr	missense_variant	Exon 7 of 10		NP_001121077.1
LIPA	NM_001288979.2	c.335T>A	p.Phe112Tyr	missense_variant	Exon 5 of 8		NP_001275908.1
LIPA	XM_024448023.2	c.683T>A	p.Phe228Tyr	missense_variant	Exon 7 of 10		XP_024303791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIPA	ENST00000336233.10	c.683T>A	p.Phe228Tyr	missense_variant	Exon 7 of 10	1	NM_000235.4	ENSP00000337354.5
LIPA	ENST00000428800.5	c.683T>A	p.Phe228Tyr	missense_variant	Exon 6 of 7	1		ENSP00000388415.1
LIPA	ENST00000371837.5	c.515T>A	p.Phe172Tyr	missense_variant	Exon 6 of 9	2		ENSP00000360903.1
LIPA	ENST00000456827.5	c.335T>A	p.Phe112Tyr	missense_variant	Exon 5 of 8	3		ENSP00000413019.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 250964 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461820 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.;T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D;T
M_CAP	Benign	0.078	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	3.2	M;.;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.0	N;N;.;N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D;D;.;D
Sift4G	Uncertain	0.0040	D;D;D;.
Polyphen		0.79	P;P;.;.
Vest4		0.53
MutPred		0.56		Gain of catalytic residue at L223 (P = 0.0525);.;.;Gain of catalytic residue at L223 (P = 0.0525);
MVP		0.94
MPC		0.61
ClinPred		0.93	D
GERP RS		4.4
Varity_R		0.70
gMVP		0.72

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: rs2228159; hg19: chr10-90983580;