9-130480405-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_054012.4(ASS1):​c.794G>T​(p.Arg265Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R265C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

ASS1
NM_054012.4 missense

Scores

12
5
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 7.44
Variant links:
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 11 ACMG points.

PM1
In a strand (size 6) in uniprot entity ASSY_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_054012.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr9-130480404-C-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.996
PP5
Variant 9-130480405-G-T is Pathogenic according to our data. Variant chr9-130480405-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1019261.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ASS1NM_054012.4 linkc.794G>T p.Arg265Leu missense_variant Exon 11 of 15 ENST00000352480.10 NP_446464.1 P00966Q5T6L4
ASS1NM_000050.4 linkc.794G>T p.Arg265Leu missense_variant Exon 12 of 16 NP_000041.2 P00966Q5T6L4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ASS1ENST00000352480.10 linkc.794G>T p.Arg265Leu missense_variant Exon 11 of 15 1 NM_054012.4 ENSP00000253004.6 P00966

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Citrullinemia type I Pathogenic:1
May 10, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:1
May 08, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Citrullinemia Uncertain:1
Aug 31, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine with leucine at codon 265 of the ASS1 protein (p.Arg265Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with ASS1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg265 amino acid residue in ASS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18473344, 28132756, 30285816). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
D;D;D
Eigen
Pathogenic
0.76
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.83
.;.;T
M_CAP
Pathogenic
0.76
D
MetaRNN
Pathogenic
1.0
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.2
M;M;M
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-6.7
D;D;D
REVEL
Pathogenic
0.95
Sift
Uncertain
0.014
D;D;D
Sift4G
Uncertain
0.0040
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.96
MutPred
0.97
Loss of MoRF binding (P = 0.0423);Loss of MoRF binding (P = 0.0423);Loss of MoRF binding (P = 0.0423);
MVP
0.97
MPC
1.0
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.90
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs398123131; hg19: chr9-133355792; API