10-89222514-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_StrongBP6BP7BS2_Supporting

The NM_000235.4(LIPA):​c.891C>T​(p.Ser297=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000587 in 1,603,646 control chromosomes in the GnomAD database, including 2 homozygotes. 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 0.00041 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00060 ( 2 hom. )

Consequence

LIPA
NM_000235.4 synonymous

Scores

1
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:4

Conservation

PhyloP100: -0.617
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.71).
BP6
Variant 10-89222514-G-A is Benign according to our data. Variant chr10-89222514-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 301575.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5}. Variant chr10-89222514-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-0.617 with no splicing effect.
BS2
High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LIPANM_000235.4 linkuse as main transcriptc.891C>T p.Ser297= synonymous_variant 8/10 ENST00000336233.10 NP_000226.2
LIPANM_001127605.3 linkuse as main transcriptc.891C>T p.Ser297= synonymous_variant 8/10 NP_001121077.1
LIPANM_001288979.2 linkuse as main transcriptc.543C>T p.Ser181= synonymous_variant 6/8 NP_001275908.1
LIPAXM_024448023.2 linkuse as main transcriptc.891C>T p.Ser297= synonymous_variant 8/10 XP_024303791.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LIPAENST00000336233.10 linkuse as main transcriptc.891C>T p.Ser297= synonymous_variant 8/101 NM_000235.4 ENSP00000337354 P1P38571-1
LIPAENST00000371837.5 linkuse as main transcriptc.723C>T p.Ser241= synonymous_variant 7/92 ENSP00000360903 P38571-2
LIPAENST00000456827.5 linkuse as main transcriptc.543C>T p.Ser181= synonymous_variant 6/83 ENSP00000413019
LIPAENST00000428800.5 linkuse as main transcript downstream_gene_variant 1 ENSP00000388415

Frequencies

GnomAD3 genomes
AF:
0.000414
AC:
63
AN:
152182
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000720
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:
0.000662
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000287
AC:
72
AN:
251174
Hom.:
0
AF XY:
0.000317
AC XY:
43
AN XY:
135766
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000289
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:
0.000511
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000605
AC:
878
AN:
1451346
Hom.:
2
Cov.:
28
AF XY:
0.000570
AC XY:
412
AN XY:
722792
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.000291
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:
0.000759
Gnomad4 OTH exome
AF:
0.000400
GnomAD4 genome
AF:
0.000414
AC:
63
AN:
152300
Hom.:
0
Cov.:
32
AF XY:
0.000336
AC XY:
25
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.000168
Gnomad4 AMR
AF:
0.000719
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000662
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000403
Hom.:
0
Bravo
AF:
0.000487
EpiCase
AF:
0.000927
EpiControl
AF:
0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Lysosomal acid lipase deficiency Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitterclinical testingCounsylMar 07, 2018- -
not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 28, 2016- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxOct 02, 2020This variant is associated with the following publications: (PMID: 28502505) -
Wolman disease Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 06, 2024- -
LIPA-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesApr 20, 2021This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 15, 2023This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.71
CADD
Benign
4.5
DANN
Uncertain
0.99
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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.

Other links and lift over

dbSNP: rs145066614; hg19: chr10-90982271; API