10-89247603-T-G

Position:

chr10-89247603-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000235.4(LIPA):c.46A>C(p.Thr16Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 1,610,980 control chromosomes in the GnomAD database, including 77,838 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T16T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.26 ( 5848 hom., cov: 29)

Exomes 𝑓: 0.31 ( 71990 hom. )

Consequence

LIPA
NM_000235.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.00200

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0055990517).

BP6

Variant 10-89247603-T-G is Benign according to our data. Variant chr10-89247603-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 195049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-89247603-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LIPA	NM_000235.4 linkuse as main transcript	c.46A>C	p.Thr16Pro	missense_variant	2/10	ENST00000336233.10
LIPA	NM_001127605.3 linkuse as main transcript	c.46A>C	p.Thr16Pro	missense_variant	2/10
LIPA	XM_024448023.2 linkuse as main transcript	c.46A>C	p.Thr16Pro	missense_variant	2/10
LIPA	NM_001288979.2 linkuse as main transcript	c.-120+4134A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIPA	ENST00000336233.10 linkuse as main transcript	c.46A>C	p.Thr16Pro	missense_variant	2/10	1	NM_000235.4	P1	P38571-1

Frequencies

GnomAD3 genomes

AF:

0.262

AC:

39685

AN:

151432

Hom.:

5829

Cov.:

show subpopulations

Gnomad AFR

AF:

0.129

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.329

Gnomad ASJ

AF:

0.339

Gnomad EAS

AF:

0.318

Gnomad SAS

AF:

0.416

Gnomad FIN

AF:

0.334

Gnomad MID

AF:

0.358

Gnomad NFE

AF:

0.298

Gnomad OTH

AF:

0.271

GnomAD3 exomes

AF:

0.322

AC:

80785

AN:

251232

Hom.:

13726

AF XY:

0.327

AC XY:

44434

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.123

Gnomad AMR exome

AF:

0.389

Gnomad ASJ exome

AF:

0.324

Gnomad EAS exome

AF:

0.304

Gnomad SAS exome

AF:

0.417

Gnomad FIN exome

AF:

0.342

Gnomad NFE exome

AF:

0.302

Gnomad OTH exome

AF:

0.322

GnomAD4 exome

AF:

0.309

AC:

451410

AN:

1459430

Hom.:

71990

Cov.:

AF XY:

0.313

AC XY:

227227

AN XY:

726138

show subpopulations

Gnomad4 AFR exome

AF:

0.123

Gnomad4 AMR exome

AF:

0.386

Gnomad4 ASJ exome

AF:

0.331

Gnomad4 EAS exome

AF:

0.262

Gnomad4 SAS exome

AF:

0.415

Gnomad4 FIN exome

AF:

0.349

Gnomad4 NFE exome

AF:

0.302

Gnomad4 OTH exome

AF:

0.318

GnomAD4 genome

AF:

0.262

AC:

39730

AN:

151550

Hom.:

5848

Cov.:

AF XY:

0.264

AC XY:

19519

AN XY:

74022

show subpopulations

Gnomad4 AFR

AF:

0.130

Gnomad4 AMR

AF:

0.330

Gnomad4 ASJ

AF:

0.339

Gnomad4 EAS

AF:

0.317

Gnomad4 SAS

AF:

0.416

Gnomad4 FIN

AF:

0.334

Gnomad4 NFE

AF:

0.298

Gnomad4 OTH

AF:

0.270

Alfa

AF:

0.294

Hom.:

15771

Bravo

AF:

0.254

TwinsUK

AF:

0.310

AC:

1148

ALSPAC

AF:

0.305

AC:

1174

ESP6500AA

AF:

0.129

AC:

568

ESP6500EA

AF:

0.298

AC:

2566

ExAC

AF:

0.316

AC:

38377

Asia WGS

AF:

0.379

AC:

1318

AN:

3478

EpiCase

AF:

0.303

EpiControl

AF:

0.302

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lysosomal acid lipase deficiency

Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Jul 06, 2022	- -

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 27, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Wolman disease

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 22395809, 31645127, 29196158, 28279971) -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2018

This alteration is classified as 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

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;.;T

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.29

T;T;T

MetaRNN

Benign

0.0056

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;.;.

MutationTaster

Benign

1.0

P;P;P;P;P;P;P

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.19

Sift

Benign

0.24

T;T;T

Sift4G

Benign

0.14

T;.;.

Polyphen

0.0020

B;.;.

Vest4

0.068

MPC

0.48

ClinPred

0.017

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.20

gMVP

0.56

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.

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