rs3802656

Positions:

• chr10-89215892-G-A

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.966+46C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,248,724 control chromosomes in the GnomAD database, including 39,451 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (7240 hom., cov: 32)
  • Exomes 𝑓: 0.23 (32211 hom.)
• Consequence: LIPA NM_000235.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.270

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=-0.81).
• BP6: Variant 10-89215892-G-A is Benign according to our data. Variant chr10-89215892-G-A is described in ClinVar as [Benign]. Clinvar id is 255613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-89215892-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIPA	NM_000235.4	c.966+46C>T		intron_variant		ENST00000336233.10
LIPA	NM_001127605.3	c.966+46C>T		intron_variant
LIPA	NM_001288979.2	c.618+46C>T		intron_variant
LIPA	XM_024448023.2	c.966+46C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIPA	ENST00000336233.10	c.966+46C>T		intron_variant		1	NM_000235.4	P1
LIPA	ENST00000371837.5	c.798+46C>T		intron_variant		2
LIPA	ENST00000456827.5	c.618+46C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.283 AC: 43069 AN: 151992 Hom.: 7217 Cov.: 32

Gnomad AFR AF: 0.462

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.0331

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.328

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.262

GnomAD3 exomes AF: 0.211 AC: 52798 AN: 250550 Hom.: 6541 AF XY: 0.211 AC XY: 28602 AN XY: 135728

Gnomad AFR exome AF: 0.459

Gnomad AMR exome AF: 0.140

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.0290

Gnomad SAS exome AF: 0.181

Gnomad FIN exome AF: 0.173

Gnomad NFE exome AF: 0.243

Gnomad OTH exome AF: 0.219

GnomAD4 exome AF: 0.233 AC: 255184 AN: 1096612 Hom.: 32211 Cov.: 15 AF XY: 0.231 AC XY: 129985 AN XY: 562368

Gnomad4 AFR exome AF: 0.464

Gnomad4 AMR exome AF: 0.147

Gnomad4 ASJ exome AF: 0.202

Gnomad4 EAS exome AF: 0.0255

Gnomad4 SAS exome AF: 0.182

Gnomad4 FIN exome AF: 0.180

Gnomad4 NFE exome AF: 0.249

Gnomad4 OTH exome AF: 0.237

GnomAD4 genome AF: 0.284 AC: 43139 AN: 152112 Hom.: 7240 Cov.: 32 AF XY: 0.276 AC XY: 20509 AN XY: 74358

Gnomad4 AFR AF: 0.462

Gnomad4 AMR AF: 0.181

Gnomad4 ASJ AF: 0.206

Gnomad4 EAS AF: 0.0332

Gnomad4 SAS AF: 0.172

Gnomad4 FIN AF: 0.172

Gnomad4 NFE AF: 0.247

Gnomad4 OTH AF: 0.260

Alfa AF: 0.256 Hom.: 1315

Bravo AF: 0.292

Asia WGS AF: 0.158 AC: 552 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Lysosomal acid lipase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	12
DANN	Benign	0.63

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: rs3802656; hg19: chr10-90975649;