9-130452232-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_054012.4(ASS1):​c.4T>C​(p.Ser2Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

ASS1
NM_054012.4 missense

Scores

7
12

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 2.73

Publications

0 publications found
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]
ASS1 Gene-Disease associations (from GenCC):
  • citrullinemia type I
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, G2P
  • acute neonatal citrullinemia type I
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • adult-onset citrullinemia type I
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 49 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.75759 (below the threshold of 3.09). Trascript score misZ: 1.8061 (below the threshold of 3.09). GenCC associations: The gene is linked to citrullinemia type I, adult-onset citrullinemia type I, acute neonatal citrullinemia type I.
BP4
Computational evidence support a benign effect (MetaRNN=0.41699976).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ASS1NM_054012.4 linkc.4T>C p.Ser2Pro missense_variant Exon 2 of 15 ENST00000352480.10 NP_446464.1 P00966Q5T6L4
ASS1NM_000050.4 linkc.4T>C p.Ser2Pro missense_variant Exon 3 of 16 NP_000041.2 P00966Q5T6L4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ASS1ENST00000352480.10 linkc.4T>C p.Ser2Pro missense_variant Exon 2 of 15 1 NM_054012.4 ENSP00000253004.6 P00966

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Citrullinemia type I Uncertain:1
May 05, 2025
Natera, Inc.
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.096
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Uncertain
-0.010
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.41
T;T;T;.;.
Eigen
Benign
-0.43
Eigen_PC
Benign
-0.30
FATHMM_MKL
Benign
0.75
D
LIST_S2
Benign
0.74
.;.;T;T;T
M_CAP
Uncertain
0.22
D
MetaRNN
Benign
0.42
T;T;T;T;T
MetaSVM
Uncertain
0.63
D
MutationAssessor
Benign
-0.32
N;N;N;.;.
PhyloP100
2.7
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-1.9
N;N;N;N;D
REVEL
Uncertain
0.47
Sift
Benign
0.15
T;T;T;T;T
Sift4G
Benign
0.073
T;T;T;D;D
Polyphen
0.31
B;B;B;.;.
Vest4
0.48
MutPred
0.30
Gain of catalytic residue at S2 (P = 0.0102);Gain of catalytic residue at S2 (P = 0.0102);Gain of catalytic residue at S2 (P = 0.0102);Gain of catalytic residue at S2 (P = 0.0102);Gain of catalytic residue at S2 (P = 0.0102);
MVP
0.96
MPC
0.33
ClinPred
0.54
D
GERP RS
2.5
PromoterAI
0.022
Neutral
Varity_R
0.27
gMVP
0.49
Mutation Taster
=84/16
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

hg19: chr9-133327619; API