chr10-89245129-A-G

Variant names:

• chr10-89245129-A-G
• rs2246942
• NM_000235.4:c.229+547T>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+547T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.384 in 152,042 control chromosomes in the GnomAD database, including 11,539 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 0.38 (11539 hom., cov: 33)
• Consequence: LIPA NM_000235.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.866
• Publications: 31 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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPA	NM_000235.4	c.229+547T>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+547T>C		intron_variant	Intron 3 of 9	1	NM_000235.4	ENSP00000337354.5

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58355 AN: 151924 Hom.: 11509 Cov.: 33

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.430

Gnomad ASJ AF: 0.362

Gnomad EAS AF: 0.337

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.344

Gnomad OTH AF: 0.379

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

GnomAD4 genome AF: 0.384 AC: 58429 AN: 152042 Hom.: 11539 Cov.: 33 AF XY: 0.387 AC XY: 28748 AN XY: 74294

African (AFR) AF: 0.423 AC: 17542 AN: 41462

American (AMR) AF: 0.432 AC: 6595 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.362 AC: 1255 AN: 3470

East Asian (EAS) AF: 0.336 AC: 1742 AN: 5182

South Asian (SAS) AF: 0.526 AC: 2533 AN: 4820

European-Finnish (FIN) AF: 0.408 AC: 4308 AN: 10546

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.344 AC: 23384 AN: 67968

Other (OTH) AF: 0.378 AC: 796 AN: 2108

Alfa AF: 0.351 Hom.: 12613

Bravo AF: 0.386

Asia WGS AF: 0.480 AC: 1667 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.4
DANN	Benign	0.59
PhyloP100		0.87
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: rs2246942; hg19: chr10-91004886;