NM_001371904.1:c.990_993delAACA

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_001371904.1(APOA5):c.990_993delAACA(p.Asp332ValfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,144 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

APOA5
NM_001371904.1 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: -0.0360

Variant links:

Genes affected

APOA5 (HGNC:17288): (apolipoprotein A5) The protein encoded by this gene is an apolipoprotein that plays an important role in regulating the plasma triglyceride levels, a major risk factor for coronary artery disease. It is a component of high density lipoprotein and is highly similar to a rat protein that is upregulated in response to liver injury. Mutations in this gene have been associated with hypertriglyceridemia and hyperlipoproteinemia type 5. This gene is located proximal to the apolipoprotein gene cluster on chromosome 11q23. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Oct 2009]

APOA5 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.101 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-116790235-CTGTT-C is Pathogenic according to our data. Variant chr11-116790235-CTGTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 978324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOA5	NM_001371904.1 link	c.990_993delAACA	p.Asp332ValfsTer5	frameshift_variant	Exon 3 of 3	ENST00000227665.9	NP_001358833.1
APOA5	NM_001166598.2 link	c.990_993delAACA	p.Asp332ValfsTer5	frameshift_variant	Exon 4 of 4		NP_001160070.1	Q6Q788A0A0B4RUS7
APOA5	NM_052968.5 link	c.990_993delAACA	p.Asp332ValfsTer5	frameshift_variant	Exon 4 of 4		NP_443200.2	Q6Q788A0A0B4RUS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
APOA5	ENST00000227665.9 link	c.990_993delAACA	p.Asp332ValfsTer5	frameshift_variant	Exon 3 of 3	1	NM_001371904.1	ENSP00000227665.4	Q6Q788
APOA5	ENST00000433069.2 link	c.990_993delAACA	p.Asp332ValfsTer5	frameshift_variant	Exon 4 of 4	1		ENSP00000399701.2	Q6Q788
APOA5	ENST00000673688.1 link	c.1074_1077delAACA	p.Asp360ValfsTer5	frameshift_variant	Exon 3 of 3			ENSP00000501141.1	A0A669KB69
APOA5	ENST00000542499.5 link	c.990_993delAACA	p.Asp332ValfsTer5	frameshift_variant	Exon 4 of 4	5		ENSP00000445002.1	Q6Q788

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251382

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461890

Hom.:

AF XY:

0.00000825

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial type 5 hyperlipoproteinemia

Pathogenic:2

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with susceptibility to hypertriglyceridemia (MIM#145750) and hyperchylomicronemia (MIM#144650). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant and recessive inheritance modes have been reported, with biallelic variants associated with severe disease (PMID: 16531747). (I) 0112 - The condition associated with this gene has incomplete penetrance. Unaffected carriers of pathogenic variants have been described (PMID: 16200213). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0252 - This variant is homozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 (2 heterozygotes, 0 homozygotes). (SP) 0600 - Variant truncates the annotated apolipoprotein domain (Pfam). (I) 0704 - Another truncating variant comparable to the one identified in this case has limited previous evidence for pathogenicity. A downstream truncating variant was reported heterozygous in an individual with severe hypertriglyceridaemia (PMID: 21993410). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in heterozygous, homozygous, and compound heterozygous individuals with hypertriglyceridaemia (ClinVar, PMID: 24591733, 24291057, 30420299). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional assays indicate this variant is stably expressed but has impaired binding to receptors (PMID: 23307945). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic). (I) -

not provided

Pathogenic:2

Jan 21, 2020

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Asp332Valfs*5) in the APOA5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 35 amino acid(s) of the APOA5 protein. This variant is present in population databases (rs774150500, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with APOA5-related conditions (PMID: 23307945, 24591733, 29748148, 30420299; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Q330Q fs X6. ClinVar contains an entry for this variant (Variation ID: 978324). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects APOA5 function (PMID: 23307945). For these reasons, this variant has been classified as Pathogenic. -

Hypertriglyceridemia 1

Pathogenic:1

Feb 14, 2022

DASA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.990_993del;p.(Asp332Valfs*5) is a null frameshift variant in the APOA5 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1_moderate. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 23307945) - PS3_supporting. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (PMID: 24591733; 28951076; 24291057) - PS4_moderate. This variant is not present in population databases (rs774150500, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The p.(Asp332Valfs*5) was detected in trans with a pathogenic variant (PMID: 24591733) - PM3. In summary, the currently available evidence indicates that the variant is likely pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Feb 23, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.990_993delAACA variant, located in coding exon 3 of the APOA5 gene, results from a deletion of 4 nucleotides at nucleotide positions 990 to 993, causing a translational frameshift with a predicted alternate stop codon (p.D332Vfs*5). This alteration occurs at the 3' terminus of theAPOA5 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 35 amino acids (9.6%) of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This variant has been detected in the homozygous state and the in the compound heterozygous state with a second APOA5 pathogenic variant in individuals with severe hypertriglyceridemia (Mendoza-Barberá E et al. J Lipid Res, 2013 Mar;54:649-661; Hooper AJ et al. Ann Clin Biochem, 2014 Jul;51:485-9). This variant has also been detected in the heterozygous state in additional hypertriglyceridemia cohorts (Martín-Campos JM et al. Clin Chim Acta, 2014 Feb;429:61-8; Jin JL et al. EBioMedicine, 2018 Dec;38:171-177). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over