rs121908640

chr9-130494983-C-Gchr9-130494983-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_054012.4(ASS1):c.1087C>G(p.Arg363Gly) variant causes a missense change. 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. R363Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASS1 NM_054012.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 3.90

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a strand (size 7) in uniprot entity ASSY_HUMAN there are 13 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 chr9-130494984-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 9-130494983-C-G is Pathogenic according to our data. Variant chr9-130494983-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 847892.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr9-130494983-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASS1	NM_054012.4	c.1087C>G	p.Arg363Gly	missense_variant	13/15	ENST00000352480.10
ASS1	NM_000050.4	c.1087C>G	p.Arg363Gly	missense_variant	14/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASS1	ENST00000352480.10	c.1087C>G	p.Arg363Gly	missense_variant	13/15	1	NM_054012.4	P1
ASS1	ENST00000372393.7	c.1087C>G	p.Arg363Gly	missense_variant	14/16	5		P1
ASS1	ENST00000372394.5	c.1087C>G	p.Arg363Gly	missense_variant	14/16	2		P1
ASS1	ENST00000372386.6	n.358C>G		non_coding_transcript_exon_variant	4/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Citrullinemia Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Apr 11, 2019	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. This variant disrupts the p.Arg363 amino acid residue in ASS1. Another variant that disrupt this residue has been determined to be pathogenic (PMID: 16124451, 28111830, 26117549, 2358466, 14680976, 12815590, 25537548). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 has been observed in an individual affected with citrullinemia type I (PMID: 28111830). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 363 of the ASS1 protein (p.Arg363Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 04, 2023	Variant summary: ASS1 c.1087C>G (p.Arg363Gly) results in a non-conservative amino acid change in the encoded protein sequence, altering a highly conserved amino acid in a mutational hot spot, and other missense variants affecting this and nearby amino acids (R363Q/L/W, G362V) are found in association with Citrullinaemia (HGMD). One of these variants (c.1087C>T, p.Arg363Trp) has been classified as pathogenic by our laboratory, while another (c.1088G>A, p.Arg363Gln) is classified as pathogenic/likely pathogenic in ClinVar based on several other labs. These suggest the variant likely effects a functionally important region of the protein. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250206 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1087C>G has been reported in the literature in an individual affected with severe Citrullinemia Type 1 (Gao_2003, Dies-Fernandez_2017), and this patient was reported as compound heterozygous with another (likely) pathogenic truncating variant. This suggests the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	1.0	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H;H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.8	D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.98
MutPred		0.98		Gain of catalytic residue at S365 (P = 0.0708);Gain of catalytic residue at S365 (P = 0.0708);Gain of catalytic residue at S365 (P = 0.0708);
MVP		0.99
MPC		1.0
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.99
gMVP		0.95

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

LitVar

Other links and lift over

dbSNP: rs121908640; hg19: chr9-133370370;