9-130494984-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5

The NM_054012.4(ASS1):​c.1088G>T​(p.Arg363Leu) 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 Lovd as Pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R363G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

ASS1
NM_054012.4 missense

Scores

12
5
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.29
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 13 ACMG points.

PS1
Transcript NM_054012.4 (ASS1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
In a strand (size 7) in uniprot entity ASSY_HUMAN there are 7 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 chr9-130494983-C-G is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
Variant 9-130494984-G-T is Pathogenic according to our data. Variant chr9-130494984-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ASS1NM_054012.4 linkc.1088G>T p.Arg363Leu missense_variant Exon 13 of 15 ENST00000352480.10 NP_446464.1 P00966Q5T6L4
ASS1NM_000050.4 linkc.1088G>T p.Arg363Leu missense_variant Exon 14 of 16 NP_000041.2 P00966Q5T6L4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ASS1ENST00000352480.10 linkc.1088G>T p.Arg363Leu missense_variant Exon 13 of 15 1 NM_054012.4 ENSP00000253004.6 P00966
ASS1ENST00000372393.7 linkc.1088G>T p.Arg363Leu missense_variant Exon 14 of 16 5 ENSP00000361469.2 P00966
ASS1ENST00000372394.5 linkc.1088G>T p.Arg363Leu missense_variant Exon 14 of 16 2 ENSP00000361471.1 P00966
ASS1ENST00000372386.6 linkn.359G>T non_coding_transcript_exon_variant Exon 4 of 6 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
D;D;D
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.86
.;.;D
M_CAP
Pathogenic
0.72
D
MetaRNN
Pathogenic
1.0
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.3
M;M;M
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-6.8
D;D;D
REVEL
Pathogenic
0.98
Sift
Uncertain
0.0060
D;D;D
Sift4G
Uncertain
0.0040
D;D;D
Polyphen
0.98
D;D;D
Vest4
0.95
MutPred
0.97
Loss of phosphorylation at S365 (P = 0.0559);Loss of phosphorylation at S365 (P = 0.0559);Loss of phosphorylation at S365 (P = 0.0559);
MVP
0.99
MPC
0.98
ClinPred
1.0
D
GERP RS
4.6
Varity_R
0.91
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-133370371; API