rs2246833

Positions:

• chr10-89246097-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 684269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-89246097-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.509 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIPA	NM_000235.4	c.112-304G>A		intron_variant		ENST00000336233.10	NP_000226.2
LIPA	NM_001127605.3	c.112-304G>A		intron_variant			NP_001121077.1
LIPA	NM_001288979.2	c.-120+5640G>A		intron_variant			NP_001275908.1
LIPA	XM_024448023.2	c.112-304G>A		intron_variant			XP_024303791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIPA	ENST00000336233.10	c.112-304G>A		intron_variant		1	NM_000235.4	ENSP00000337354.5

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

Gnomad4 AFR AF: 0.411

Gnomad4 AMR AF: 0.430

Gnomad4 ASJ AF: 0.361

Gnomad4 EAS AF: 0.337

Gnomad4 SAS AF: 0.526

Gnomad4 FIN AF: 0.406

Gnomad4 NFE AF: 0.340

Gnomad4 OTH AF: 0.371

Alfa AF: 0.363 Hom.: 5708

Bravo AF: 0.380

Asia WGS AF: 0.479 AC: 1668 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Wolman disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2246833; hg19: chr10-91005854;