10-89391165-G-T

Variant names:

• chr10-89391165-G-T
• rs304478
• NM_001440819.1:c.-2+21626C>A

Variant summary

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

The NM_001440819.1(LIPA):​c.-2+21626C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.623 in 152,130 control chromosomes in the GnomAD database, including 31,977 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 0.62 (31977 hom., cov: 33)
• Consequence: LIPA NM_001440819.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0150
• Publications: 13 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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.874 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440819.1. 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_001440819.1		c.-2+21626C>A		intron	N/A	NP_001427748.1
	LIPA	NM_001440820.1		c.-2+21576C>A		intron	N/A	NP_001427749.1
	LIPA	NM_001440821.1		c.-99+21626C>A		intron	N/A	NP_001427750.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPA	ENST00000371837.5	TSL:2	c.61+21626C>A		intron	N/A	ENSP00000360903.1

Frequencies

GnomAD3 genomes AF: 0.623 AC: 94633 AN: 152012 Hom.: 31936 Cov.: 33

Gnomad AFR AF: 0.882

Gnomad AMI AF: 0.659

Gnomad AMR AF: 0.579

Gnomad ASJ AF: 0.608

Gnomad EAS AF: 0.856

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.497

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.482

Gnomad OTH AF: 0.617

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

GnomAD4 genome AF: 0.623 AC: 94721 AN: 152130 Hom.: 31977 Cov.: 33 AF XY: 0.624 AC XY: 46431 AN XY: 74382

African (AFR) AF: 0.882 AC: 36603 AN: 41514

American (AMR) AF: 0.578 AC: 8837 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 2110 AN: 3472

East Asian (EAS) AF: 0.856 AC: 4437 AN: 5186

South Asian (SAS) AF: 0.551 AC: 2655 AN: 4818

European-Finnish (FIN) AF: 0.497 AC: 5250 AN: 10570

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.482 AC: 32755 AN: 67964

Other (OTH) AF: 0.618 AC: 1305 AN: 2110

Alfa AF: 0.535 Hom.: 68553

Bravo AF: 0.639

Asia WGS AF: 0.686 AC: 2383 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.7
DANN	Benign	0.65
PhyloP100		-0.015
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs304478; hg19: chr10-91150922;