rs771937610

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_054012.4(ASS1):c.1088G>A(p.Arg363Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,040 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R363L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

ASS1
NM_054012.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

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]

ASS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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, 0.993

PP5

Variant 9-130494984-G-A is Pathogenic according to our data. 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. Variant chr9-130494984-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASS1	NM_054012.4 link	c.1088G>A	p.Arg363Gln	missense_variant	Exon 13 of 15	ENST00000352480.10	NP_446464.1	P00966Q5T6L4
ASS1	NM_000050.4 link	c.1088G>A	p.Arg363Gln	missense_variant	Exon 14 of 16		NP_000041.2	P00966Q5T6L4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ASS1	ENST00000352480.10 link	c.1088G>A	p.Arg363Gln	missense_variant	Exon 13 of 15	1	NM_054012.4	ENSP00000253004.6	P00966
ASS1	ENST00000372393.7 link	c.1088G>A	p.Arg363Gln	missense_variant	Exon 14 of 16	5		ENSP00000361469.2	P00966
ASS1	ENST00000372394.5 link	c.1088G>A	p.Arg363Gln	missense_variant	Exon 14 of 16	2		ENSP00000361471.1	P00966
ASS1	ENST00000372386.6 link	n.359G>A		non_coding_transcript_exon_variant	Exon 4 of 6	3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250050

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135322

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1460884

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726748

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Citrullinemia type I

Pathogenic:3

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant p.R363Q in ASS1 (NM_054012.4) has been previously reported in an individual affected with ASS1-related conditins (Gao et al, 2003). The p.R363Q variant has a gnomAD frequency of 0.0003999 % and is novel (not in any individuals) in 1000 Genomes. There is a small physicochemical difference between arginine and glutamine, which is not likely to impact secondary protein structure as these residues share similar properties. The p.R363Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 363 of ASS1 is conserved in all mammalian species. The nucleotide c.1088 in ASS1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. The observed variant is also detected in the spouse. -

Dec 29, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 16, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Aug 29, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 24, 2021

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in other individuals reported to have citrullinemia who either did not have a second variant identified in the ASS1 gene or for whom detailed clinical information was not provided (Haberle et al., 2010; Zielonka et al., 2019); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 30285816, 24508627, 19006241, 12815590, 28111830, 31469252, 20005624) -

Citrullinemia

Pathogenic:1

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 363 of the ASS1 protein (p.Arg363Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with citrullinemia type I (PMID: 30285816, 31469252; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 203631). 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%. This variant disrupts the p.Arg363 amino acid residue in ASS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2358466, 12815590, 14680976, 16124451, 25537548, 26117549, 28111830). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

ASS1-related disorder

Pathogenic:1

Sep 25, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ASS1 c.1088G>A variant is predicted to result in the amino acid substitution p.Arg363Gln. This variant has been reported along with a second pathogenic variant in multiple individuals with citrullinemia, and was in confirmed to be in the compound heterozygous state in at least one of the reported individuals (Gao et al. 2003. PubMed ID: 12815590; Table S1 in Diez-Fernandez et al. 2017. PubMed ID: 28111830; Bijarnia-Mahay et al. 2018. PubMed ID: 30285816; PreventionGenetics internal data). When expressed along with a second known pathogenic variant (p.Gly390Arg) in a biallelic expression system, activity of the argininosuccinate synthetase enzyme was reduced to <20% of control (Zielonka et al. 2019. PubMed ID: 31469252). Alternate substitutions at this location (p.Arg363Gly, p.Arg363Leu, p.Arg363Trp) have been reported in affected patients, with p.Arg363Trp being a particularly common recurrent pathogenic variant (See Table S1 in Diez-Fernandez et al. 2017. PubMed ID: 28111830). The p.Arg363 amino acid is moderately conserved, and is located at the dimer interface where it is thought to play an important role in dimer/tetramer formation (Gao et al. 2003. PubMed ID: 12815590; Diez-Fernandez et al. 2017. PubMed ID: 28111830). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;D;D

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

.;.;D

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

H;H;H

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.9

D;D;D

REVEL

Pathogenic

0.93

Sift

Benign

0.053

T;T;T

Sift4G

Uncertain

0.028

D;D;D

Polyphen

0.91

P;P;P

Vest4

0.98

MutPred

0.97

Loss of phosphorylation at S365 (P = 0.0626);Loss of phosphorylation at S365 (P = 0.0626);Loss of phosphorylation at S365 (P = 0.0626);

MVP

0.98

MPC

0.48

ClinPred

0.99

GERP RS

4.6

Varity_R

0.93

gMVP

0.88

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over