rs771794639

chr9-130464126-C-Gchr9-130464126-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_054012.4(ASS1):c.379C>G(p.Arg127Gly) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R127L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ASS1 NM_054012.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.81

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 12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain 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 chr9-130464127-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 623334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 9-130464126-C-G is Pathogenic according to our data. Variant chr9-130464126-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 649412.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASS1	NM_054012.4	c.379C>G	p.Arg127Gly	missense_variant	5/15	ENST00000352480.10
ASS1	NM_000050.4	c.379C>G	p.Arg127Gly	missense_variant	6/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASS1	ENST00000352480.10	c.379C>G	p.Arg127Gly	missense_variant	5/15	1	NM_054012.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Citrullinemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2018

This variant disrupts the Arg127 amino acid residue in ASS1. Other variant(s) that disrupt this residue have been observed in individuals with ASS1-related conditions (PMID: 23099195, 19006241, 14680976), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 combination with another ASS1 variant in an individual affected with citrullinemia type I (PMID: 23246278). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 127 of the ASS1 protein (p.Arg127Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D;D;D;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.4	H;H;H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.6	D;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.98
MutPred		0.97		Loss of catalytic residue at R127 (P = 0.062);Loss of catalytic residue at R127 (P = 0.062);Loss of catalytic residue at R127 (P = 0.062);Loss of catalytic residue at R127 (P = 0.062);
MVP		0.98
MPC		1.1
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.99
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs771794639; hg19: chr9-133339513;