NM_000235.4:c.539-5C>T

Variant names:

• chr10-89225233-G-A
• rs2297472
• NM_000235.4:c.539-5C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000235.4(LIPA):​c.539-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,613,070 control chromosomes in the GnomAD database, including 48,404 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4540 hom., cov: 32)
  • Exomes 𝑓: 0.22 (43864 hom.)
• Consequence: LIPA NM_000235.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003292
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.224
• Publications: 25 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 10-89225233-G-A is Benign according to our data. Variant chr10-89225233-G-A is described in ClinVar as Benign. ClinVar VariationId is 255610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.709 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPA	NM_000235.4	MANE Select	c.539-5C>T		splice_region intron	N/A	NP_000226.2
	LIPA	NM_001440836.1		c.671-5C>T		splice_region intron	N/A	NP_001427765.1
	LIPA	NM_001440837.1		c.560-5C>T		splice_region intron	N/A	NP_001427766.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPA	ENST00000336233.10	TSL:1 MANE Select	c.539-5C>T		splice_region intron	N/A	ENSP00000337354.5
	LIPA	ENST00000428800.5	TSL:1	c.539-5C>T		splice_region intron	N/A	ENSP00000388415.1
	LIPA	ENST00000868683.1		c.560-5C>T		splice_region intron	N/A	ENSP00000538742.1

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31723 AN: 152006 Hom.: 4533 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.729

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.221

GnomAD2 exomes AF: 0.289 AC: 72636 AN: 251068 AF XY: 0.282

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.472

Gnomad ASJ exome AF: 0.237

Gnomad EAS exome AF: 0.738

Gnomad FIN exome AF: 0.261

Gnomad NFE exome AF: 0.193

Gnomad OTH exome AF: 0.263

GnomAD4 exome AF: 0.220 AC: 321511 AN: 1460946 Hom.: 43864 Cov.: 34 AF XY: 0.222 AC XY: 161564 AN XY: 726822

African (AFR) AF: 0.0998 AC: 3341 AN: 33466

American (AMR) AF: 0.453 AC: 20255 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 6116 AN: 26130

East Asian (EAS) AF: 0.729 AC: 28921 AN: 39692

South Asian (SAS) AF: 0.315 AC: 27139 AN: 86236

European-Finnish (FIN) AF: 0.259 AC: 13811 AN: 53404

Middle Eastern (MID) AF: 0.264 AC: 1524 AN: 5768

European-Non Finnish (NFE) AF: 0.185 AC: 206116 AN: 1111180

Other (OTH) AF: 0.237 AC: 14288 AN: 60352

GnomAD4 genome AF: 0.209 AC: 31753 AN: 152124 Hom.: 4540 Cov.: 32 AF XY: 0.218 AC XY: 16200 AN XY: 74358

African (AFR) AF: 0.106 AC: 4393 AN: 41500

American (AMR) AF: 0.321 AC: 4913 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 823 AN: 3472

East Asian (EAS) AF: 0.729 AC: 3767 AN: 5168

South Asian (SAS) AF: 0.327 AC: 1574 AN: 4820

European-Finnish (FIN) AF: 0.255 AC: 2694 AN: 10558

Middle Eastern (MID) AF: 0.298 AC: 87 AN: 292

European-Non Finnish (NFE) AF: 0.189 AC: 12829 AN: 67998

Other (OTH) AF: 0.222 AC: 468 AN: 2112

Alfa AF: 0.195 Hom.: 10778

Bravo AF: 0.215

Asia WGS AF: 0.471 AC: 1634 AN: 3478

EpiCase AF: 0.195

EpiControl AF: 0.188

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	6.6
DANN	Benign	0.85
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs2297472; hg19: chr10-90984990; COSMIC: COSV51079077;