rs2246833

Variant names:

• chr10-89246097-C-T
• rs2246833
• NM_000235.4:c.112-304G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000235.4(LIPA):​c.112-304G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 151,904 control chromosomes in the GnomAD database, including 11,201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.38 (11201 hom., cov: 32)
• Consequence: LIPA NM_000235.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.200
• Publications: 61 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: Myriad Women's Health, Labcorp Genetics (formerly Invitae), Ambry Genetics, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-89246097-C-T is Benign according to our data. Variant chr10-89246097-C-T is described in ClinVar as Benign. ClinVar VariationId is 684269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.509 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.112-304G>A		intron	N/A	NP_000226.2	P38571-1
	LIPA	NM_001440836.1		c.244-304G>A		intron	N/A	NP_001427765.1
	LIPA	NM_001440837.1		c.112-304G>A		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.112-304G>A		intron	N/A	ENSP00000337354.5	P38571-1
	LIPA	ENST00000428800.5	TSL:1	c.112-304G>A		intron	N/A	ENSP00000388415.1	Q5T073
	LIPA	ENST00000868683.1		c.112-304G>A		intron	N/A	ENSP00000538742.1

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57444 AN: 151784 Hom.: 11173 Cov.: 32

Gnomad AFR AF: 0.410

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.406

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.372

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

GnomAD4 genome AF: 0.379 AC: 57516 AN: 151904 Hom.: 11201 Cov.: 32 AF XY: 0.382 AC XY: 28312 AN XY: 74210

African (AFR) AF: 0.411 AC: 16998 AN: 41402

American (AMR) AF: 0.430 AC: 6552 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 1252 AN: 3464

East Asian (EAS) AF: 0.337 AC: 1743 AN: 5170

South Asian (SAS) AF: 0.526 AC: 2533 AN: 4818

European-Finnish (FIN) AF: 0.406 AC: 4270 AN: 10528

Middle Eastern (MID) AF: 0.435 AC: 127 AN: 292

European-Non Finnish (NFE) AF: 0.340 AC: 23113 AN: 67958

Other (OTH) AF: 0.371 AC: 782 AN: 2110

Alfa AF: 0.366 Hom.: 8793

Bravo AF: 0.380

Asia WGS AF: 0.479 AC: 1668 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Wolman disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.1
DANN	Benign	0.39
PhyloP100		-0.20
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2246833;

hg19: chr10-91005854;