10-89247603-T-G

Variant names:

• chr10-89247603-T-G
• rs1051338
• NM_000235.4:c.46A>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

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. 15/21 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.00200
• Publications: 94 publications found

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 Gene-Disease associations (from GenCC):

• lysosomal acid lipase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• cholesteryl ester storage disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Wolman disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 39 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 0.22832 (below the threshold of 3.09). Trascript score misZ: 0.63421 (below the threshold of 3.09). GenCC associations: The gene is linked to cholesteryl ester storage disease, lysosomal acid lipase deficiency, Wolman disease.
• 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 Benign/Likely_benign. ClinVar VariationId is 195049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000235.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPA	NM_000235.4	MANE Select	c.46A>C	p.Thr16Pro	missense	Exon 2 of 10	NP_000226.2
	LIPA	NM_001440836.1		c.178A>C	p.Thr60Pro	missense	Exon 3 of 11	NP_001427765.1
	LIPA	NM_001440837.1		c.46A>C	p.Thr16Pro	missense	Exon 2 of 10	NP_001427766.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPA	ENST00000336233.10	TSL:1 MANE Select	c.46A>C	p.Thr16Pro	missense	Exon 2 of 10	ENSP00000337354.5
	LIPA	ENST00000428800.5	TSL:1	c.46A>C	p.Thr16Pro	missense	Exon 1 of 7	ENSP00000388415.1
	LIPA	ENST00000868683.1		c.46A>C	p.Thr16Pro	missense	Exon 2 of 10	ENSP00000538742.1

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39685 AN: 151432 Hom.: 5829 Cov.: 29

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

GnomAD2 exomes AF: 0.322 AC: 80785 AN: 251232 AF XY: 0.327

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 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.: 33 AF XY: 0.313 AC XY: 227227 AN XY: 726138

African (AFR) AF: 0.123 AC: 4129 AN: 33464

American (AMR) AF: 0.386 AC: 17274 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 8632 AN: 26118

East Asian (EAS) AF: 0.262 AC: 10416 AN: 39688

South Asian (SAS) AF: 0.415 AC: 35793 AN: 86188

European-Finnish (FIN) AF: 0.349 AC: 18625 AN: 53406

Middle Eastern (MID) AF: 0.343 AC: 1980 AN: 5768

European-Non Finnish (NFE) AF: 0.302 AC: 335404 AN: 1109786

Other (OTH) AF: 0.318 AC: 19157 AN: 60312

GnomAD4 genome AF: 0.262 AC: 39730 AN: 151550 Hom.: 5848 Cov.: 29 AF XY: 0.264 AC XY: 19519 AN XY: 74022

African (AFR) AF: 0.130 AC: 5364 AN: 41352

American (AMR) AF: 0.330 AC: 5018 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 1177 AN: 3468

East Asian (EAS) AF: 0.317 AC: 1633 AN: 5148

South Asian (SAS) AF: 0.416 AC: 1993 AN: 4796

European-Finnish (FIN) AF: 0.334 AC: 3482 AN: 10424

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.298 AC: 20245 AN: 67854

Other (OTH) AF: 0.270 AC: 568 AN: 2102

Alfa AF: 0.287 Hom.: 20178

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Lysosomal acid lipase deficiency (5)
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Wolman disease (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	10
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.0020
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.19
Sift	Benign	0.24	T
Sift4G	Benign	0.14	T
Polyphen		0.0020	B
Vest4		0.068
MPC		0.48
ClinPred		0.017	T
GERP RS		3.7
PromoterAI		0.00070	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.20
gMVP		0.56
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1051338; hg19: chr10-91007360; COSMIC: COSV51078248;