NM_000235.4:c.676-42G>A

Variant names:

• chr10-89223872-C-T
• rs1556478
• NM_000235.4:c.676-42G>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.676-42G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 1,603,140 control chromosomes in the GnomAD database, including 99,079 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9600 hom., cov: 32)
  • Exomes 𝑓: 0.34 (89479 hom.)
• Consequence: LIPA NM_000235.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.00700
• Publications: 19 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 10-89223872-C-T is Benign according to our data. Variant chr10-89223872-C-T is described in ClinVar as Benign. ClinVar VariationId is 255611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.749 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPA	NM_000235.4	MANE Select	c.676-42G>A		intron	N/A	NP_000226.2
	LIPA	NM_001440836.1		c.808-42G>A		intron	N/A	NP_001427765.1
	LIPA	NM_001440837.1		c.697-42G>A		intron	N/A	NP_001427766.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPA	ENST00000336233.10	TSL:1 MANE Select	c.676-42G>A		intron	N/A	ENSP00000337354.5
	LIPA	ENST00000428800.5	TSL:1	c.676-42G>A		intron	N/A	ENSP00000388415.1
	LIPA	ENST00000868683.1		c.697-42G>A		intron	N/A	ENSP00000538742.1

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51687 AN: 151872 Hom.: 9586 Cov.: 32

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.297

Gnomad AMR AF: 0.424

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.769

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.335

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.345

GnomAD2 exomes AF: 0.407 AC: 101717 AN: 249890 AF XY: 0.405

Gnomad AFR exome AF: 0.283

Gnomad AMR exome AF: 0.572

Gnomad ASJ exome AF: 0.381

Gnomad EAS exome AF: 0.774

Gnomad FIN exome AF: 0.339

Gnomad NFE exome AF: 0.308

Gnomad OTH exome AF: 0.389

GnomAD4 exome AF: 0.337 AC: 488448 AN: 1451150 Hom.: 89479 Cov.: 29 AF XY: 0.341 AC XY: 246462 AN XY: 722626

African (AFR) AF: 0.286 AC: 9519 AN: 33260

American (AMR) AF: 0.555 AC: 24786 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.376 AC: 9807 AN: 26052

East Asian (EAS) AF: 0.775 AC: 30744 AN: 39650

South Asian (SAS) AF: 0.488 AC: 42020 AN: 86038

European-Finnish (FIN) AF: 0.339 AC: 18048 AN: 53280

Middle Eastern (MID) AF: 0.417 AC: 2395 AN: 5750

European-Non Finnish (NFE) AF: 0.299 AC: 329735 AN: 1102424

Other (OTH) AF: 0.357 AC: 21394 AN: 60010

GnomAD4 genome AF: 0.340 AC: 51750 AN: 151990 Hom.: 9600 Cov.: 32 AF XY: 0.348 AC XY: 25873 AN XY: 74282

African (AFR) AF: 0.292 AC: 12087 AN: 41458

American (AMR) AF: 0.425 AC: 6496 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 1353 AN: 3468

East Asian (EAS) AF: 0.769 AC: 3965 AN: 5154

South Asian (SAS) AF: 0.495 AC: 2384 AN: 4812

European-Finnish (FIN) AF: 0.335 AC: 3531 AN: 10540

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.306 AC: 20800 AN: 67980

Other (OTH) AF: 0.346 AC: 727 AN: 2104

Alfa AF: 0.325 Hom.: 38333

Bravo AF: 0.347

Asia WGS AF: 0.586 AC: 2037 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Lysosomal acid lipase deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.5
DANN	Benign	0.51
PhyloP100		-0.0070
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

Other links and lift over

dbSNP: rs1556478; hg19: chr10-90983629; COSMIC: COSV51079074; COSMIC: COSV51079074;