10-89214840-C-T

Variant names:

• chr10-89214840-C-T
• rs750001661
• NM_000235.4:c.1188G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_000235.4(LIPA):​c.1188G>A​(p.Arg396Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000441 in 1,588,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: LIPA NM_000235.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.309
• Publications: 0 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 -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).
• BP6: Variant 10-89214840-C-T is Benign according to our data. Variant chr10-89214840-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 558136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.309 with no splicing effect.

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.1188G>A	p.Arg396Arg	synonymous	Exon 10 of 10	NP_000226.2
	LIPA	NM_001440836.1		c.1320G>A	p.Arg440Arg	synonymous	Exon 11 of 11	NP_001427765.1
	LIPA	NM_001440837.1		c.1209G>A	p.Arg403Arg	synonymous	Exon 10 of 10	NP_001427766.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPA	ENST00000336233.10	TSL:1 MANE Select	c.1188G>A	p.Arg396Arg	synonymous	Exon 10 of 10	ENSP00000337354.5
	LIPA	ENST00000868683.1		c.1209G>A	p.Arg403Arg	synonymous	Exon 10 of 10	ENSP00000538742.1
	LIPA	ENST00000938134.1		c.1209G>A	p.Arg403Arg	synonymous	Exon 10 of 10	ENSP00000608193.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249528 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000418 AC: 6 AN: 1436582 Hom.: 0 Cov.: 26 AF XY: 0.00000140 AC XY: 1 AN XY: 716370

African (AFR) AF: 0.00 AC: 0 AN: 32946

American (AMR) AF: 0.00 AC: 0 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25966

East Asian (EAS) AF: 0.00 AC: 0 AN: 39544

South Asian (SAS) AF: 0.00 AC: 0 AN: 85636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00000551 AC: 6 AN: 1089312

Other (OTH) AF: 0.00 AC: 0 AN: 59500

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74330

African (AFR) AF: 0.00 AC: 0 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	-	1	Cholesteryl ester storage disease (1)
-	-	1	Wolman disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	8.2
DANN	Benign	0.67
PhyloP100		0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs750001661; hg19: chr10-90974597;