9-130494984-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_054012.4(ASS1):​c.1088G>C​(p.Arg363Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R363L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

ASS1
NM_054012.4 missense

Scores

13
5
1

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

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 chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.995

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ASS1NM_054012.4 linkc.1088G>C p.Arg363Pro missense_variant Exon 13 of 15 ENST00000352480.10 NP_446464.1 P00966Q5T6L4
ASS1NM_000050.4 linkc.1088G>C p.Arg363Pro 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>C p.Arg363Pro missense_variant Exon 13 of 15 1 NM_054012.4 ENSP00000253004.6 P00966
ASS1ENST00000372393.7 linkc.1088G>C p.Arg363Pro missense_variant Exon 14 of 16 5 ENSP00000361469.2 P00966
ASS1ENST00000372394.5 linkc.1088G>C p.Arg363Pro missense_variant Exon 14 of 16 2 ENSP00000361471.1 P00966
ASS1ENST00000372386.6 linkn.359G>C non_coding_transcript_exon_variant Exon 4 of 6 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460884
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726748
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
1.0
D;D;D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.98
.;.;D
M_CAP
Pathogenic
0.67
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Pathogenic
4.2
H;H;H
PrimateAI
Uncertain
0.69
T
PROVEAN
Pathogenic
-6.8
D;D;D
REVEL
Pathogenic
0.99
Sift
Uncertain
0.0010
D;D;D
Sift4G
Uncertain
0.0030
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.98
MutPred
0.94
Loss of MoRF binding (P = 0.0709);Loss of MoRF binding (P = 0.0709);Loss of MoRF binding (P = 0.0709);
MVP
0.99
MPC
1.1
ClinPred
1.0
D
GERP RS
4.6
Varity_R
0.99
gMVP
0.98

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