chr10-89223823-A-G

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_000235.4(LIPA):​c.683T>C​(p.Phe228Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000126 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: LIPA NM_000235.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• 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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.021826178).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00065 (99/152296) while in subpopulation AFR AF= 0.00214 (89/41558). AF 95% confidence interval is 0.00178. There are 0 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPA	NM_000235.4	c.683T>C	p.Phe228Ser	missense_variant	Exon 7 of 10	ENST00000336233.10	NP_000226.2
LIPA	NM_001127605.3	c.683T>C	p.Phe228Ser	missense_variant	Exon 7 of 10		NP_001121077.1
LIPA	NM_001288979.2	c.335T>C	p.Phe112Ser	missense_variant	Exon 5 of 8		NP_001275908.1
LIPA	XM_024448023.2	c.683T>C	p.Phe228Ser	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>C	p.Phe228Ser	missense_variant	Exon 7 of 10	1	NM_000235.4	ENSP00000337354.5
LIPA	ENST00000428800.5	c.683T>C	p.Phe228Ser	missense_variant	Exon 6 of 7	1		ENSP00000388415.1
LIPA	ENST00000371837.5	c.515T>C	p.Phe172Ser	missense_variant	Exon 6 of 9	2		ENSP00000360903.1
LIPA	ENST00000456827.5	c.335T>C	p.Phe112Ser	missense_variant	Exon 5 of 8	3		ENSP00000413019.2

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000207 AC: 52 AN: 250964 Hom.: 0 AF XY: 0.000206 AC XY: 28 AN XY: 135748

Gnomad AFR exome AF: 0.00253

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000718 AC: 105 AN: 1461820 Hom.: 0 Cov.: 32 AF XY: 0.0000729 AC XY: 53 AN XY: 727214

Gnomad4 AFR exome AF: 0.00233

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000650 AC: 99 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000698 AC XY: 52 AN XY: 74482

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000111 Hom.: 0

Bravo AF: 0.000722

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000222 AC: 27

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lysosomal acid lipase deficiency Uncertain:2

May 10, 2023

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 09, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:2

Jul 05, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 13, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1 -

not specified Uncertain:1

Dec 01, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LIPA c.683T>C (p.Phe228Ser) results in a non-conservative amino acid change located in the alpha/beta hydrolase fold-1 domain (IPR000073) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 250964 control chromosomes, predominantly at a frequency of 0.0025 within the African or African-American subpopulation in the gnomAD database. This frequency is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in LIPA causing Lysosomal Acid Lipase Deficiency (0.00021 vs 0.0027), suggesting it could be a benign polymorphism found predominately in individuals of African ancestry. c.683T>C has been reported in the literature in the heterozygous state in two individuals affected with familial hypercholesterolemia, but no diagnosis of Lysosomal Acid Lipase Deficiency (Sjouke_2016). This report does not provide unequivocal conclusions about association of the variant with Lysosomal Acid Lipase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32041611, 27423329). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Three submitters classified the variant as uncertain significance and one classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

LIPA-related disorder Uncertain:1

Jan 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The LIPA c.683T>C variant is predicted to result in the amino acid substitution p.Phe228Ser. This variant has been reported in two individuals with hypercholesterolaemia and in an individual from a cohort being studied for dyslipidemia (Table 2, Sjouke et al. 2016. PubMed ID: 27423329; Table S4, Dron et al. 2020. PubMed ID: 32041611). This variant is reported in 0.25% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype Uncertain:1

Nov 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.F228S variant (also known as c.683T>C), located in coding exon 6 of the LIPA gene, results from a T to C substitution at nucleotide position 683. The phenylalanine at codon 228 is replaced by serine, an amino acid with highly dissimilar properties. This variant has been reported in a familial hypercholesterolemia (FH) cohort (Sjouke B et al. Atherosclerosis, 2016 Aug;251:263-265). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Wolman disease Benign:1

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.;T;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.022	T;T;T;T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.8	M;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-4.9	D;D;.;D
REVEL	Uncertain	0.52
Sift	Benign	0.071	T;T;.;T
Sift4G	Uncertain	0.053	T;D;T;.
Polyphen		0.55	P;D;.;.
Vest4		0.90
MVP		0.93
MPC		0.81
ClinPred		0.13	T
GERP RS		4.4
Varity_R		0.73
gMVP		0.88

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;