rs142637046
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000048.4(ASL):c.446+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000912 in 1,612,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000092 ( 0 hom. )
Consequence
ASL
NM_000048.4 splice_donor
NM_000048.4 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 8.85
Genes affected
ASL (HGNC:746): (argininosuccinate lyase) This gene encodes a member of the lyase 1 family. The encoded protein forms a cytosolic homotetramer and primarily catalyzes the reversible hydrolytic cleavage of argininosuccinate into arginine and fumarate, an essential step in the liver in detoxifying ammonia via the urea cycle. Mutations in this gene result in the autosomal recessive disorder argininosuccinic aciduria, or argininosuccinic acid lyase deficiency. A nontranscribed pseudogene is also located on the long arm of chromosome 22. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06953405 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.5, offset of 36, new splice context is: gagGTgtga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-66083175-G-A is Pathogenic according to our data. Variant chr7-66083175-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 92361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-66083175-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ASL | NM_000048.4 | c.446+1G>A | splice_donor_variant | ENST00000304874.14 | NP_000039.2 | |||
| ASL | NM_001024943.2 | c.446+1G>A | splice_donor_variant | NP_001020114.1 | ||||
| ASL | NM_001024944.2 | c.446+1G>A | splice_donor_variant | NP_001020115.1 | ||||
| ASL | NM_001024946.2 | c.446+1G>A | splice_donor_variant | NP_001020117.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ASL | ENST00000304874.14 | c.446+1G>A | splice_donor_variant | 1 | NM_000048.4 | ENSP00000307188 | P1 |
Frequencies
GnomAD3 genomes 0.0000790 AC: 12AN: 151984Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000441 AC: 11AN: 249560Hom.: 0 AF XY: 0.0000665 AC XY: 9AN XY: 135250
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GnomAD4 exome AF: 0.0000925 AC: 135AN: 1460040Hom.: 0 Cov.: 31 AF XY: 0.0000964 AC XY: 70AN XY: 726306
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GnomAD4 genome 0.0000789 AC: 12AN: 152102Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74362
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Argininosuccinate lyase deficiency Pathogenic:10
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Mar 10, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000092361). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 12, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 2024 | This sequence change affects a donor splice site in intron 6 of the ASL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ASL are known to be pathogenic (PMID: 2263616, 24166829). This variant is present in population databases (rs142637046, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with argininosuccinate lyase (ASL) deficiency (PMID: 12384776). This variant is also known as IVS5+1G>A. ClinVar contains an entry for this variant (Variation ID: 92361). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 24, 2023 | The ASL c.446+1G>A variant (rs142637046) is reported in the literature in many individuals with argininosuccinic aciduria (Linnebank 2002, Toquet 2021). This variant is reported in ClinVar (Variation ID: 92361) and is found in the general population with an overall allele frequency of 0.005% (13/280,896 alleles) in the Genome Aggregation Database (v2.1.1). This variant disrupts the canonical splice donor site of intron 6, and experimental evidence found this variant results in the skipping of exon 5 (Linnebank 2002). Based on available information, this variant is considered to be pathogenic. References: Linnebank M et al. Argininosuccinate lyase (ASL) deficiency: mutation analysis in 27 patients and a completed structure of the human ASL gene. Hum Genet. 2002 Oct;111(4-5):350-9. PMID: 12384776. Toquet S et al. Adult-onset diagnosis of urea cycle disorders: Results of a French cohort of 71 patients. J Inherit Metab Dis. 2021 Sep;44(5):1199-1214. PMID: 34014557. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2002 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Jul 28, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 05, 2017 | Variant summary: The ASL c.446+1G>A variant involves the alteration of a conserved intronic nucleotide that 5/5 splice prediction tools predict a significant impact on splicing, which is supported by a functional study, Linnebank_2002. This variant was found in 6/117678 control chromosomes at a frequency of 0.000051, which does not exceed the estimated maximal expected allele frequency of a pathogenic ASL variant (0.0042258). The variant of interest (legacy name IVS5+1G>A) has been reported in multiple affected individuals as both compound heterozygotes and homozygotes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 10, 2021 | NM_001024943.1(ASL):c.446+1G>A is a canonical splice variant classified as pathogenic in the context of argininosuccinic aciduria. c.446+1G>A has been observed in cases with relevant disease (PMID: 12384776). Functional assessments of this variant are available in the literature (PMID: 12384776). c.446+1G>A has been observed in population frequency databases (gnomAD: NFE <0.001%). In summary, NM_001024943.1(ASL):c.446+1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 08, 2021 | Canonical splice site variant predicted to result in a null allele and deletion of the upstream exon in a gene for which loss-of-function is a known mechanism of disease (Linnebank et al., 2002); Identified in a patient with late onset argininosuccinic aciduria who also harbored a second ASL variant (Baruteau et al., 2017); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25087612, 25525159, 24166829, 12384776, 28251416, 31589614) - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 22, 2013 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D;D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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