chr10-89247582-C-T

Variant names:

• chr10-89247582-C-T
• rs1051339
• NM_000235.4:c.67G>A

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.67G>A​(p.Gly23Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,612,192 control chromosomes in the GnomAD database, including 9,505 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. G23G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.13 (1590 hom., cov: 30)
  • Exomes 𝑓: 0.10 (7915 hom.)
• Consequence: LIPA NM_000235.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.386
• Publications: 23 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 Submitted by: ClinGen
• lysosomal acid lipase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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=0.0035889745).
• BP6: Variant 10-89247582-C-T is Benign according to our data. Variant chr10-89247582-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.219 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.67G>A	p.Gly23Arg	missense	Exon 2 of 10	NP_000226.2	P38571-1
	LIPA	NM_001440836.1		c.199G>A	p.Gly67Arg	missense	Exon 3 of 11	NP_001427765.1
	LIPA	NM_001440837.1		c.67G>A	p.Gly23Arg	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.67G>A	p.Gly23Arg	missense	Exon 2 of 10	ENSP00000337354.5	P38571-1
	LIPA	ENST00000428800.5	TSL:1	c.67G>A	p.Gly23Arg	missense	Exon 1 of 7	ENSP00000388415.1	Q5T073
	LIPA	ENST00000868683.1		c.67G>A	p.Gly23Arg	missense	Exon 2 of 10	ENSP00000538742.1

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19710 AN: 151678 Hom.: 1588 Cov.: 30

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.0916

Gnomad EAS AF: 0.0576

Gnomad SAS AF: 0.0573

Gnomad FIN AF: 0.0521

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.124

GnomAD2 exomes AF: 0.0948 AC: 23828 AN: 251382 AF XY: 0.0916

Gnomad AFR exome AF: 0.226

Gnomad AMR exome AF: 0.0742

Gnomad ASJ exome AF: 0.104

Gnomad EAS exome AF: 0.0553

Gnomad FIN exome AF: 0.0521

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.100 AC: 146658 AN: 1460396 Hom.: 7915 Cov.: 30 AF XY: 0.0989 AC XY: 71849 AN XY: 726598

African (AFR) AF: 0.221 AC: 7381 AN: 33422

American (AMR) AF: 0.0770 AC: 3442 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0978 AC: 2555 AN: 26120

East Asian (EAS) AF: 0.0594 AC: 2357 AN: 39688

South Asian (SAS) AF: 0.0607 AC: 5235 AN: 86230

European-Finnish (FIN) AF: 0.0552 AC: 2947 AN: 53406

Middle Eastern (MID) AF: 0.110 AC: 634 AN: 5768

European-Non Finnish (NFE) AF: 0.104 AC: 115659 AN: 1110712

Other (OTH) AF: 0.107 AC: 6448 AN: 60332

GnomAD4 genome AF: 0.130 AC: 19722 AN: 151796 Hom.: 1590 Cov.: 30 AF XY: 0.125 AC XY: 9250 AN XY: 74200

African (AFR) AF: 0.222 AC: 9198 AN: 41368

American (AMR) AF: 0.101 AC: 1536 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.0916 AC: 318 AN: 3470

East Asian (EAS) AF: 0.0576 AC: 297 AN: 5160

South Asian (SAS) AF: 0.0567 AC: 273 AN: 4812

European-Finnish (FIN) AF: 0.0521 AC: 547 AN: 10494

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7068 AN: 67936

Other (OTH) AF: 0.123 AC: 258 AN: 2106

Alfa AF: 0.114 Hom.: 4325

Bravo AF: 0.140

TwinsUK AF: 0.102 AC: 380

ALSPAC AF: 0.103 AC: 396

ESP6500AA AF: 0.226 AC: 997

ESP6500EA AF: 0.106 AC: 912

ExAC AF: 0.101 AC: 12225

Asia WGS AF: 0.0660 AC: 230 AN: 3478

EpiCase AF: 0.108

EpiControl AF: 0.111

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.28
DANN	Benign	0.49
DEOGEN2	Benign	0.072	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.39
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.13
Sift	Benign	0.59	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.035
MutPred		0.12		Loss of glycosylation at S22 (P = 0.0317)
MPC		0.17
ClinPred		0.000031	T
GERP RS		-4.1
PromoterAI		0.0048	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.031
gMVP		0.43
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1051339; hg19: chr10-91007339; COSMIC: COSV51078800;