rs1029074

Variant names:

• chr10-89239279-A-G
• rs1029074
• NM_000235.4:c.229+6397T>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.229+6397T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 152,130 control chromosomes in the GnomAD database, including 8,583 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 0.30 (8583 hom., cov: 32)
• Consequence: LIPA NM_000235.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.35
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.528 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPA	NM_000235.4	c.229+6397T>C		intron_variant	Intron 3 of 9	ENST00000336233.10	NP_000226.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIPA	ENST00000336233.10	c.229+6397T>C		intron_variant	Intron 3 of 9	1	NM_000235.4	ENSP00000337354.5

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45886 AN: 152012 Hom.: 8569 Cov.: 32

Gnomad AFR AF: 0.534

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.246

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.271

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.284

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

GnomAD4 genome AF: 0.302 AC: 45949 AN: 152130 Hom.: 8583 Cov.: 32 AF XY: 0.300 AC XY: 22291 AN XY: 74372

African (AFR) AF: 0.534 AC: 22150 AN: 41466

American (AMR) AF: 0.246 AC: 3765 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 769 AN: 3470

East Asian (EAS) AF: 0.110 AC: 567 AN: 5178

South Asian (SAS) AF: 0.271 AC: 1308 AN: 4826

European-Finnish (FIN) AF: 0.184 AC: 1950 AN: 10586

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.215 AC: 14595 AN: 67986

Other (OTH) AF: 0.287 AC: 607 AN: 2112

Alfa AF: 0.241 Hom.: 8316

Bravo AF: 0.319

Asia WGS AF: 0.241 AC: 843 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.041
DANN	Benign	0.33
PhyloP100		-1.3
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: rs1029074; hg19: chr10-90999036;