10-89222130-T-G

Variant names:

• chr10-89222130-T-G
• rs7922269
• NM_000235.4:c.894+381A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000235.4(LIPA):​c.894+381A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 151,134 control chromosomes in the GnomAD database, including 4,782 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.20 (4782 hom., cov: 32)
• Consequence: LIPA NM_000235.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0550
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.745 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.894+381A>C		intron	N/A	NP_000226.2	P38571-1
	LIPA	NM_001440836.1		c.1026+381A>C		intron	N/A	NP_001427765.1
	LIPA	NM_001440837.1		c.915+381A>C		intron	N/A	NP_001427766.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPA	ENST00000336233.10	TSL:1 MANE Select	c.894+381A>C		intron	N/A	ENSP00000337354.5	P38571-1
	LIPA	ENST00000868683.1		c.915+381A>C		intron	N/A	ENSP00000538742.1
	LIPA	ENST00000938134.1		c.915+381A>C		intron	N/A	ENSP00000608193.1

Frequencies

GnomAD3 genomes AF: 0.198 AC: 29926 AN: 151018 Hom.: 4770 Cov.: 32

Gnomad AFR AF: 0.0610

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.764

Gnomad SAS AF: 0.471

Gnomad FIN AF: 0.301

Gnomad MID AF: 0.309

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.206

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.198 AC: 29959 AN: 151134 Hom.: 4782 Cov.: 32 AF XY: 0.213 AC XY: 15726 AN XY: 73862

African (AFR) AF: 0.0612 AC: 2500 AN: 40876

American (AMR) AF: 0.334 AC: 5083 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 796 AN: 3472

East Asian (EAS) AF: 0.765 AC: 3947 AN: 5162

South Asian (SAS) AF: 0.472 AC: 2256 AN: 4782

European-Finnish (FIN) AF: 0.301 AC: 3152 AN: 10466

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

European-Non Finnish (NFE) AF: 0.170 AC: 11525 AN: 67842

Other (OTH) AF: 0.208 AC: 436 AN: 2100

Alfa AF: 0.188 Hom.: 5471

Bravo AF: 0.196

Asia WGS AF: 0.543 AC: 1885 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.8
DANN	Benign	0.64
PhyloP100		-0.055
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs7922269; hg19: chr10-90981887; COSMIC: COSV51078377; COSMIC: COSV51078377;