rs143508372
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Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong
The NM_000048.4(ASL):āc.571C>Gā(p.Arg191Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,438,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 0.0000021 ( 0 hom. )
Consequence
ASL
NM_000048.4 missense
NM_000048.4 missense
Scores
6
8
5
Clinical Significance
Conservation
PhyloP100: 1.78
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 13 ACMG points.
PM1
In a helix (size 25) in uniprot entity ARLY_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000048.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.801
PP5
Variant 7-66086790-C-G is Pathogenic according to our data. Variant chr7-66086790-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 692055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ASL | NM_000048.4 | c.571C>G | p.Arg191Gly | missense_variant | 8/17 | ENST00000304874.14 | NP_000039.2 | |
ASL | NM_001024943.2 | c.571C>G | p.Arg191Gly | missense_variant | 7/16 | NP_001020114.1 | ||
ASL | NM_001024944.2 | c.571C>G | p.Arg191Gly | missense_variant | 7/15 | NP_001020115.1 | ||
ASL | NM_001024946.2 | c.524+128C>G | intron_variant | NP_001020117.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ASL | ENST00000304874.14 | c.571C>G | p.Arg191Gly | missense_variant | 8/17 | 1 | NM_000048.4 | ENSP00000307188.9 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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33
GnomAD3 exomes AF: 0.00000482 AC: 1AN: 207286Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 112280
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GnomAD4 exome AF: 0.00000209 AC: 3AN: 1438498Hom.: 0 Cov.: 32 AF XY: 0.00000280 AC XY: 2AN XY: 713754
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GnomAD4 genome Cov.: 33
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33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Argininosuccinate lyase deficiency Pathogenic:2Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | May 17, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Oct 12, 2018 | This variant has not been previously reported or functionally characterized in the literature to our knowledge. However, a variant involving the same amino acid but resulting in a different missense change (p.Arg191Trp) has been previously reported in an asymptomatic patient with argininosuccinate lyase deficiency detected by newborn screening (PMID: 24166829). The c.571C>G (p.Arg191Gly) variant detected in this individual is present in the heterozygous state in the gnomAD population database at a frequency of 0.0005% (1/201720) and thus is presumed to be rare. Based on the available evidence, the c.571C>G p.Arg191Gly variant is classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 08, 2024 | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 191 of the ASL protein (p.Arg191Gly). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of ASL-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 692055). 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. This variant disrupts the p.Arg191 amino acid residue in ASL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21744316, 24166829, 31943503). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;.;M
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Pathogenic
Sift
Benign
T;T;T;T
Sift4G
Benign
T;T;T;T
Polyphen
P;P;.;.
Vest4
MutPred
Loss of methylation at R191 (P = 0.0419);Loss of methylation at R191 (P = 0.0419);.;Loss of methylation at R191 (P = 0.0419);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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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