rs121908641

Variant names:

• chr9-130499545-G-A
• rs121908641
• NM_054012.4:c.1168G>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS1 PM1 PP2 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. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. 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:21 O:1
• Conservation: PhyloP100: 7.72
• Publications: 45 publications found

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]

ASS1 Gene-Disease associations (from GenCC):

• citrullinemia type I

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, G2P
• acute neonatal citrullinemia type I

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• adult-onset citrullinemia type I

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS1: Transcript NM_054012.4 (ASS1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_054012.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 49 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.75759 (below the threshold of 3.09). Trascript score misZ: 1.8061 (below the threshold of 3.09). GenCC associations: The gene is linked to citrullinemia type I, adult-onset citrullinemia type I, acute neonatal citrullinemia type I.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 6329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_054012.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASS1	NM_054012.4	MANE Select	c.1168G>A	p.Gly390Arg	missense	Exon 14 of 15	NP_446464.1
	ASS1	NM_000050.4		c.1168G>A	p.Gly390Arg	missense	Exon 15 of 16	NP_000041.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASS1	ENST00000352480.10	TSL:1 MANE Select	c.1168G>A	p.Gly390Arg	missense	Exon 14 of 15	ENSP00000253004.6
	ASS1	ENST00000372393.7	TSL:5	c.1168G>A	p.Gly390Arg	missense	Exon 15 of 16	ENSP00000361469.2
	ASS1	ENST00000372394.5	TSL:2	c.1168G>A	p.Gly390Arg	missense	Exon 15 of 16	ENSP00000361471.1

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

GnomAD2 exomes AF: 0.000315 AC: 79 AN: 250658 AF XY: 0.000399

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33470

American (AMR) AF: 0.000224 AC: 10 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.000952 AC: 82 AN: 86098

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000322 AC: 358 AN: 1111866

Other (OTH) AF: 0.000282 AC: 17 AN: 60388

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

African (AFR) AF: 0.0000965 AC: 4 AN: 41444

American (AMR) AF: 0.000131 AC: 2 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000211 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:21 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Citrullinemia type I Pathogenic:15 Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Nov 12, 2019

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Aug 29, 2016

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

Mar 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 12, 2024

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 12, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mar 28, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Aug 09, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Feb 01, 2024

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The above variant has been reported previously in homozygous state in individual(s) affected with citrullinemia (Daou M et al 2023). In the absence of another reportable variant in ASS1 gene, the molecular diagnosis not confirmed.

Jul 22, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 04, 2023

Genomic Medicine Lab, University of California San Francisco

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 18, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 31, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM3,PP3,PP4.

not provided Pathogenic:3

Jul 10, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

Apr 20, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Citrullinemia Pathogenic:2

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.

May 01, 2025

Department of Reproductive Genetics, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This missense variant has been reported in the literature as biallelic or a compound heterozygous state in multiple individuals affected with Citrullinemia (PMID:16475226;12815590;23430935). In-silico tool predicts a pathogenic outcome for this variant. Functional studies in vitro or in vivo support that this variation can have harmful effects on genes or gene products(PMID:18473344).

Inborn genetic diseases Pathogenic:1

Feb 04, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.99		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
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs121908641; hg19: chr9-133374932;