10-89223823-A-G

Position:

chr10-89223823-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 6.50

Variant links:

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]

LIPA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
LIPA	NM_000235.4 linkuse as main transcript	c.683T>C	p.Phe228Ser	missense_variant	7/10	ENST00000336233.10	NP_000226.2	P38571-1
LIPA	NM_001127605.3 linkuse as main transcript	c.683T>C	p.Phe228Ser	missense_variant	7/10		NP_001121077.1	P38571-1
LIPA	NM_001288979.2 linkuse as main transcript	c.335T>C	p.Phe112Ser	missense_variant	5/8		NP_001275908.1	P38571A0A0A0MT32
LIPA	XM_024448023.2 linkuse as main transcript	c.683T>C	p.Phe228Ser	missense_variant	7/10		XP_024303791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LIPA	ENST00000336233.10 linkuse as main transcript	c.683T>C	p.Phe228Ser	missense_variant	7/10	1	NM_000235.4	ENSP00000337354.5	P38571-1
LIPA	ENST00000428800.5 linkuse as main transcript	c.683T>C	p.Phe228Ser	missense_variant	6/7	1		ENSP00000388415.1	Q5T073
LIPA	ENST00000371837.5 linkuse as main transcript	c.515T>C	p.Phe172Ser	missense_variant	6/9	2		ENSP00000360903.1	P38571-2
LIPA	ENST00000456827.5 linkuse as main transcript	c.335T>C	p.Phe112Ser	missense_variant	5/8	3		ENSP00000413019.2	A0A0A0MT32

Frequencies

GnomAD3 genomes

AF:

0.000657

AC:

100

AN:

152178

Hom.:

Cov.:

show subpopulations

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:

AN:

250964

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

135748

show subpopulations

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.:

Cov.:

AF XY:

0.0000729

AC XY:

AN XY:

727214

show subpopulations

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:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

74482

show subpopulations

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.:

Bravo

AF:

0.000722

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000222

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lysosomal acid lipase deficiency

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	May 10, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 09, 2017	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 13, 2024	BS1 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 01, 2023

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

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 09, 2024

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2024

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.033

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;.;T;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.78

T;T;T;T

M_CAP

Benign

0.077

MetaRNN

Benign

0.022

T;T;T;T

MetaSVM

Uncertain

0.11

MutationAssessor

Uncertain

2.8

M;.;.;.

PrimateAI

Benign

0.44

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over