rs145066614

Variant names:

• chr10-89222514-G-A
• rs145066614
• NM_000235.4:c.891C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6 BP7 BS2_Supporting

The NM_000235.4(LIPA):​c.891C>T​(p.Ser297Ser) 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:6
• Conservation: PhyloP100: -0.617
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.023).
• 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 VariationId is 301575.
• 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.

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.891C>T	p.Ser297Ser	synonymous	Exon 8 of 10	NP_000226.2	P38571-1
	LIPA	NM_001440836.1		c.1023C>T	p.Ser341Ser	synonymous	Exon 9 of 11	NP_001427765.1
	LIPA	NM_001440837.1		c.912C>T	p.Ser304Ser	synonymous	Exon 8 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.891C>T	p.Ser297Ser	synonymous	Exon 8 of 10	ENSP00000337354.5	P38571-1
	LIPA	ENST00000868683.1		c.912C>T	p.Ser304Ser	synonymous	Exon 8 of 10	ENSP00000538742.1
	LIPA	ENST00000938134.1		c.912C>T	p.Ser304Ser	synonymous	Exon 8 of 10	ENSP00000608193.1

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152182 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000287 AC: 72 AN: 251174 AF XY: 0.000317

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 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

African (AFR) AF: 0.000120 AC: 4 AN: 33222

American (AMR) AF: 0.000291 AC: 13 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 86050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.000759 AC: 837 AN: 1102506

Other (OTH) AF: 0.000400 AC: 24 AN: 60010

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74468

African (AFR) AF: 0.000168 AC: 7 AN: 41566

American (AMR) AF: 0.000719 AC: 11 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000365 Hom.: 0

Bravo AF: 0.000487

EpiCase AF: 0.000927

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	1	Lysosomal acid lipase deficiency (2)
-	1	1	Wolman disease (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Cholesteryl ester storage disease (1)
-	-	1	LIPA-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	4.5
DANN	Uncertain	0.99
PhyloP100		-0.62
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

Other links and lift over

dbSNP: rs145066614; hg19: chr10-90982271;