rs121908641
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_054012.4(ASS1):c.1168G>A(p.Gly390Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000316 in 1,613,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00032 ( 0 hom. )
Consequence
ASS1
NM_054012.4 missense
NM_054012.4 missense
Scores
16
2
1
Clinical Significance
Conservation
PhyloP100: 7.72
Genes affected
ASS1 (HGNC:758): (argininosuccinate synthase 1) The protein encoded by this gene catalyzes the penultimate step of the arginine biosynthetic pathway. There are approximately 10 to 14 copies of this gene including the pseudogenes scattered across the human genome, among which the one located on chromosome 9 appears to be the only functional gene for argininosuccinate synthetase. Mutations in the chromosome 9 copy of this gene cause citrullinemia. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
In a helix (size 19) in uniprot entity ASSY_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_054012.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.938
PP5
Variant 9-130499545-G-A is Pathogenic according to our data. Variant chr9-130499545-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-130499545-G-A is described in Lovd as [Pathogenic]. Variant chr9-130499545-G-A is described in Lovd as [Pathogenic]. Variant chr9-130499545-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ASS1 | NM_054012.4 | c.1168G>A | p.Gly390Arg | missense_variant | 14/15 | ENST00000352480.10 | NP_446464.1 | |
| ASS1 | NM_000050.4 | c.1168G>A | p.Gly390Arg | missense_variant | 15/16 | NP_000041.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ASS1 | ENST00000352480.10 | c.1168G>A | p.Gly390Arg | missense_variant | 14/15 | 1 | NM_054012.4 | ENSP00000253004.6 | ||
| ASS1 | ENST00000372393.7 | c.1168G>A | p.Gly390Arg | missense_variant | 15/16 | 5 | ENSP00000361469.2 | |||
| ASS1 | ENST00000372394.5 | c.1168G>A | p.Gly390Arg | missense_variant | 15/16 | 2 | ENSP00000361471.1 | |||
| ASS1 | ENST00000372386.6 | n.439G>A | non_coding_transcript_exon_variant | 5/6 | 3 |
Frequencies
GnomAD3 genomes 0.000263 AC: 40AN: 152172Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000315 AC: 79AN: 250658Hom.: 0 AF XY: 0.000399 AC XY: 54AN XY: 135460
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GnomAD4 exome AF: 0.000322 AC: 470AN: 1461470Hom.: 0 Cov.: 31 AF XY: 0.000326 AC XY: 237AN XY: 726970
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GnomAD4 genome 0.000263 AC: 40AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22AN XY: 74328
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:19Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Citrullinemia type I Pathogenic:14Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 28, 2024 | The p.Gly390Arg variant in AAS1 has been reported in >30 individuals with citrullinemia type I (both in the homozygous and compound heterozygous state) and segregated with disease in at least 5 affected relatives from 5 families. It is the most common variant identified in patients with the classical phenotype (Vilaseca 2001 PMID: 11708871, Gao 2003 PMID: 12815590, Berning 2008 PMID: 18473344, Engel 2009 PMID: 19006241, Laróvere 2009 PMID: 19358837, Laróvere 2012 PMID: 23430935). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 6329) and has been identified in 0.06% (3/4828) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). In vitro functional studies provide some evidence that this variant impacts protein function, demonstrating less than 2% of wild type argininosuccinate synthetase activity (Berning 2008 PMID: 18473344, Shaheen 1994PMID: 8792870) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive citrullinemia type I. ACMG/AMP Criteria applied: PM3_Very Strong, PP1_Moderate, PS3_Supporting, PP3. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 18, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 12, 2016 | Variant summary: The ASS1 c.1168G>A variant affects a conserved nucleotide, resulting in amino acid change from Gly to Arg. Gly390 is located in a-helix 12 and is important for intermolecular contact of the multimerization tails, and 5/5 in-silico tools predict damaging outcome for this variant. The enzymatic ASS activity of G390R was shown to be below 2% of the wild-type protein (Berning_HM_2008). This variant was found in 45/113324 control chromosomes at a frequency of 0.0003971, which does not exceed maximal expected frequency of a pathogenic ASS1 allele (0.0040825). This variant is reported as the most common mutation in patients with the classic phenotype of citrullinemia. In addition, several clinical laboratories classified this variant as pathogenic. Taken together, this variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 31, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM3,PP3,PP4. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The c.1168G>A (p.Gly390Arg) missense variant in ASS1 gene has been reported in homozygous state in individuals affected with citrullinemia (Laróvere et al., 2012). Experimental studies have shown that this variant disrupts the function and substantially reduces the activity of the encoded enzyme in vitro (Berning et al., 2008). This variant is reported with the allele frequency (0.03%) in the gnomad and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The amino acid Gly at position 390 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 12, 2019 | NM_000050.4(ASS1):c.1168G>A(G390R) is classified as likely pathogenic in the context of citrullinemia type 1. Sources cited for classification include the following: PMID 18473344, 16475226, 12815590, and 7557970. Classification of NM_000050.4(ASS1):c.1168G>A(G390R) is based on the following criteria: There is strong evidence of association with the variant and the relevant disease and there is functional data showing deficient protein function. Please note: this variant was assessed in the context of healthy population screening. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Apr 04, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 09, 2021 | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Aug 29, 2016 | The observed variant c.1168G>A (p.Gly390Arg) is not reported in 1000 Genomes and has a minor allele frequency of 0.00040 in ExAC databases. The in silico prediction of the variant is disease causing by MutationTaster2, damaging by SIFT and probably damaging by Polyphen2. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2009 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 20, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 10, 2021 | Published functional studies demonstrate less than 2% of wild type argininosuccinate synthetase activity (Berning et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27535533, 31469252, 31980526, 25433810, 7557970, 11941481, 30848473, 11708871, 8792870, 19006241, 12815590, 23430935, 19358837, 2358466, 28741715, 16421053, 28132756, 27287393, 22975760, 25087612, 18473344, 16475226) - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 04, 2022 | The c.1168G>A (p.G390R) alteration is located in exon 15 (coding exon 13) of the ASS1 gene. This alteration results from a G to A substitution at nucleotide position 1168, causing the glycine (G) at amino acid position 390 to be replaced by an arginine (R). Based on data from gnomAD, the A allele has an overall frequency of 0.03% (86/282044) total alleles studied. The highest observed frequency was 0.11% (32/30412) of South Asian alleles. This mutation has been reported in the homozygous and compound heterozygous states in patients with citrullinemia and is the most commonly reported mutation in multiple cohorts worldwide (Gao, 2003; Diez-Fernandez, 2017). This amino acid position is highly conserved in available vertebrate species. In vitro studies demonstrate that this mutation results in significantly reduced enzymatic activity in multiple cell types (Berning, 2008; Zielonka, 2019). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Citrullinemia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 390 of the ASS1 protein (p.Gly390Arg). This variant is present in population databases (rs121908641, gnomAD 0.1%). This missense change has been observed in individuals with citrullinemia type I (PMID: 11708871, 12815590, 18473344, 19006241, 19358837, 23430935). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6329). 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) performed at Invitae indicates that this missense variant is expected to disrupt ASS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ASS1 function (PMID: 8792870, 18473344). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;D;D
Vest4
MutPred
Gain of MoRF binding (P = 0.0528);Gain of MoRF binding (P = 0.0528);Gain of MoRF binding (P = 0.0528);
MVP
MPC
0.97
ClinPred
D
GERP RS
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gMVP
Splicing
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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