rs121908641

Positions:

• chr9-130499545-G-A
• chr9-130499545-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_054012.4(ASS1):​c.1168G>A​(p.Gly390Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000316 in 1,613,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G390G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: ASS1 NM_054012.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19 O:1
• Conservation: PhyloP100: 7.72

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 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_054012.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• PP5: Variant 9-130499545-G-A is Pathogenic according to our data. Variant chr9-130499545-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-130499545-G-A is described in Lovd as [Pathogenic]. Variant chr9-130499545-G-A is described in Lovd as [Pathogenic]. Variant chr9-130499545-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASS1	NM_054012.4	c.1168G>A	p.Gly390Arg	missense_variant	14/15	ENST00000352480.10
ASS1	NM_000050.4	c.1168G>A	p.Gly390Arg	missense_variant	15/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASS1	ENST00000352480.10	c.1168G>A	p.Gly390Arg	missense_variant	14/15	1	NM_054012.4	P1
ASS1	ENST00000372393.7	c.1168G>A	p.Gly390Arg	missense_variant	15/16	5		P1
ASS1	ENST00000372394.5	c.1168G>A	p.Gly390Arg	missense_variant	15/16	2		P1
ASS1	ENST00000372386.6	n.439G>A		non_coding_transcript_exon_variant	5/6	3

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000315 AC: 79 AN: 250658 Hom.: 0 AF XY: 0.000399 AC XY: 54 AN XY: 135460

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000322 AC: 470 AN: 1461470 Hom.: 0 Cov.: 31 AF XY: 0.000326 AC XY: 237 AN XY: 726970

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000952

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000322

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74328

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000149 Hom.: 0

Bravo AF: 0.000257

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000371 AC: 45

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Citrullinemia type I Pathogenic:14 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 09, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The c.1168G>A (p.Gly390Arg) missense variant in ASS1 gene has been reported in homozygous state in individuals affected with citrullinemia (Laróvere et al., 2012). Experimental studies have shown that this variant disrupts the function and substantially reduces the activity of the encoded enzyme in vitro (Berning et al., 2008). This variant is reported with the allele frequency (0.03%) in the gnomad and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The amino acid Gly at position 390 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 31, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM3,PP3,PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 12, 2016	Variant summary: The ASS1 c.1168G>A variant affects a conserved nucleotide, resulting in amino acid change from Gly to Arg. Gly390 is located in a-helix 12 and is important for intermolecular contact of the multimerization tails, and 5/5 in-silico tools predict damaging outcome for this variant. The enzymatic ASS activity of G390R was shown to be below 2% of the wild-type protein (Berning_HM_2008). This variant was found in 45/113324 control chromosomes at a frequency of 0.0003971, which does not exceed maximal expected frequency of a pathogenic ASS1 allele (0.0040825). This variant is reported as the most common mutation in patients with the classic phenotype of citrullinemia. In addition, several clinical laboratories classified this variant as pathogenic. Taken together, this variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	NM_000050.4(ASS1):c.1168G>A(G390R) is classified as likely pathogenic in the context of citrullinemia type 1. Sources cited for classification include the following: PMID 18473344, 16475226, 12815590, and 7557970. Classification of NM_000050.4(ASS1):c.1168G>A(G390R) is based on the following criteria: There is strong evidence of association with the variant and the relevant disease and there is functional data showing deficient protein function. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Apr 04, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Aug 29, 2016	The observed variant c.1168G>A (p.Gly390Arg) is not reported in 1000 Genomes and has a minor allele frequency of 0.00040 in ExAC databases. The in silico prediction of the variant is disease causing by MutationTaster2, damaging by SIFT and probably damaging by Polyphen2. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2024	The p.Gly390Arg variant in AAS1 has been reported in >30 individuals with citrullinemia type I (both in the homozygous and compound heterozygous state) and segregated with disease in at least 5 affected relatives from 5 families. It is the most common variant identified in patients with the classical phenotype (Vilaseca 2001 PMID: 11708871, Gao 2003 PMID: 12815590, Berning 2008 PMID: 18473344, Engel 2009 PMID: 19006241, Laróvere 2009 PMID: 19358837, Laróvere 2012 PMID: 23430935). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 6329) and has been identified in 0.06% (3/4828) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). In vitro functional studies provide some evidence that this variant impacts protein function, demonstrating less than 2% of wild type argininosuccinate synthetase activity (Berning 2008 PMID: 18473344, Shaheen 1994PMID: 8792870) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive citrullinemia type I. ACMG/AMP Criteria applied: PM3_Very Strong, PP1_Moderate, PS3_Supporting, PP3. -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2021	Published functional studies demonstrate less than 2% of wild type argininosuccinate synthetase activity (Berning et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27535533, 31469252, 31980526, 25433810, 7557970, 11941481, 30848473, 11708871, 8792870, 19006241, 12815590, 23430935, 19358837, 2358466, 28741715, 16421053, 28132756, 27287393, 22975760, 25087612, 18473344, 16475226) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 20, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2019	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 04, 2022

The c.1168G>A (p.G390R) alteration is located in exon 15 (coding exon 13) of the ASS1 gene. This alteration results from a G to A substitution at nucleotide position 1168, causing the glycine (G) at amino acid position 390 to be replaced by an arginine (R). Based on data from gnomAD, the A allele has an overall frequency of 0.03% (86/282044) total alleles studied. The highest observed frequency was 0.11% (32/30412) of South Asian alleles. This mutation has been reported in the homozygous and compound heterozygous states in patients with citrullinemia and is the most commonly reported mutation in multiple cohorts worldwide (Gao, 2003; Diez-Fernandez, 2017). This amino acid position is highly conserved in available vertebrate species. In vitro studies demonstrate that this mutation results in significantly reduced enzymatic activity in multiple cell types (Berning, 2008; Zielonka, 2019). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Citrullinemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 390 of the ASS1 protein (p.Gly390Arg). This variant is present in population databases (rs121908641, gnomAD 0.1%). This missense change has been observed in individuals with citrullinemia type I (PMID: 11708871, 12815590, 18473344, 19006241, 19358837, 23430935). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6329). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ASS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ASS1 function (PMID: 8792870, 18473344). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	D;D;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.8	H;H;H
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.5	D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.98
MutPred		0.99		Gain of MoRF binding (P = 0.0528);Gain of MoRF binding (P = 0.0528);Gain of MoRF binding (P = 0.0528);
MVP		0.99
MPC		0.97
ClinPred		0.90	D
GERP RS		3.6
Varity_R		0.98
gMVP		0.97

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: rs121908641; hg19: chr9-133374932;