rs28941473
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1PM2PP5_Very_StrongBP4
The NM_000048.4(ASL):c.532G>A(p.Val178Met) variant causes a missense change. The variant allele was found at a frequency of 0.000402 in 1,605,626 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 Pathogenic (★★).
Frequency
Genomes: 𝑓 0.00034 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00041 ( 0 hom. )
Consequence
ASL
NM_000048.4 missense
NM_000048.4 missense
Scores
5
4
9
Clinical Significance
Conservation
PhyloP100: 5.90
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 11 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000048.4
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 7-66086751-G-A is Pathogenic according to our data. Variant chr7-66086751-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-66086751-G-A is described in Lovd as [Pathogenic]. Variant chr7-66086751-G-A is described in Lovd as [Likely_pathogenic].
BP4
?
Computational evidence support a benign effect (MetaRNN=0.21561202).. Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASL | NM_000048.4 | c.532G>A | p.Val178Met | missense_variant | 8/17 | ENST00000304874.14 | |
ASL | NM_001024943.2 | c.532G>A | p.Val178Met | missense_variant | 7/16 | ||
ASL | NM_001024944.2 | c.532G>A | p.Val178Met | missense_variant | 7/15 | ||
ASL | NM_001024946.2 | c.524+89G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASL | ENST00000304874.14 | c.532G>A | p.Val178Met | missense_variant | 8/17 | 1 | NM_000048.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000342 AC: 52AN: 152154Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000294 AC: 68AN: 231396Hom.: 0 AF XY: 0.000286 AC XY: 36AN XY: 125942
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GnomAD4 exome AF: 0.000409 AC: 594AN: 1453354Hom.: 0 Cov.: 32 AF XY: 0.000364 AC XY: 263AN XY: 722556
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Argininosuccinate lyase deficiency Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 09, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 06, 2017 | Variant summary: The ASL c.532G>A (p.Val178Met) variant located in the central core heliz bundle forming the tetramer (per Balmer_2012 PMID: 24166829) causes a missense change involving a conserved nucleotide, which 3/5 in silico tools predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 35/68898 (1/1968), which does not exceed the estimated maximal expected allele frequency for a pathogenic ASL variant of 1/236. Multiple publications have reported the variant in affected individuals, who were homozygous or compound heterozygous. Functional studyies showed variant with ASL activity about 5% of WT's . In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 02, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 178 of the ASL protein (p.Val178Met). This variant is present in population databases (rs28941473, gnomAD 0.07%). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 12408190, 17326097, 19703900, 20236848). ClinVar contains an entry for this variant (Variation ID: 2402). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ASL protein function. Experimental studies have shown that this missense change affects ASL function (PMID: 19703900, 21667091, 25778938). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2002 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 26, 2019 | NM_001024943.1(ASL):c.532G>A(V178M) is classified as pathogenic in the context of argininosuccinic aciduria. Sources cited for classification include the following: PMID 12408190, 21667091, 21667091 and 24166829. Classification of NM_001024943.1(ASL):c.532G>A(V178M) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
not provided Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 11, 2022 | PP4, PM2, PM3, PS3, PS4 - |
Likely 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, Academic Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 12, 2023 | Published functional studies found this variant is associated with significantly reduced argininosuccinate lyase activity compared to wild-type (Engel et al., 2012; Doimo et al., 2012; Hu et al., 2015); This variant is associated with the following publications: (PMID: 28251416, 24166829, 17326097, 20236848, 34598035, 31589614, 22231378, 12384776, 19703900, 25778938, 31943503, 12408190, 31980526, 21667091) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 24, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D;D;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Pathogenic
D
MutationAssessor
Benign
N;N;.;N
MutationTaster
Benign
A;A;A;A
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N;N
REVEL
Pathogenic
Sift
Benign
T;T;T;T
Sift4G
Benign
T;T;T;T
Polyphen
P;P;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at