rs895822620

Positions:

• chr9-130458488-C-A
• chr9-130458488-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_054012.4(ASS1):​c.262C>A​(p.Leu88Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,384 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L88L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ASS1 NM_054012.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 3.95

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_054012.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854
• PP5: Variant 9-130458488-C-A is Pathogenic according to our data. Variant chr9-130458488-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 426661.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASS1	NM_054012.4	c.262C>A	p.Leu88Ile	missense_variant	4/15	ENST00000352480.10
ASS1	NM_000050.4	c.262C>A	p.Leu88Ile	missense_variant	5/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASS1	ENST00000352480.10	c.262C>A	p.Leu88Ile	missense_variant	4/15	1	NM_054012.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250838 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135662

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460384 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726500

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Citrullinemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 10, 2023	This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 88 of the ASS1 protein (p.Leu88Ile). This missense change has been observed in individual(s) with elevated citrulline or ASS1 enzyme deficiency in skin fibroblasts (PMID: 18925679, 25047749; Invitae). ClinVar contains an entry for this variant (Variation ID: 426661). 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. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 03, 2024	Variant summary: ASS1 c.262C>A (p.Leu88Ile) results in a conservative amino acid change located in the Arginosuccinate synthase-like, N-terminal domain (IPR048267) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250838 control chromosomes (gnomAD). c.262C>A has been reported in the literature in individuals affected with Citrullinemia (Dimmock_2008, Barends_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18925679, 25047749). ClinVar contains an entry for this variant (Variation ID: 426661). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 07, 2017

The L88I missense variant in the ASS1 gene has been previously reported in a homozygous state intwo asymptomatic individuals with abnormal newborn screening and elevated citrulline (Dimmock etal., 2008; Barends et al., 2014). The L88I variant is not observed in large population cohorts (Lek etal., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L88I variant is aconservative amino acid substitution, which is not likely to impact secondary protein structure asthese residues share similar properties. This substitution occurs at a position that is conserved acrossspecies. In silico analysis is inconsistent in its predictions as to whether or not the variant is damagingto the protein structure/function. Therefore, based on the currentlyavailable information, it is unclear whether this variant is a pathogenic variant or a rare benignvariant. -

Citrullinemia type I Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Jun 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D;D;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;H;H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.8	N;N;N;N;N
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.52
MutPred		0.64		Gain of catalytic residue at L93 (P = 0.1153);Gain of catalytic residue at L93 (P = 0.1153);Gain of catalytic residue at L93 (P = 0.1153);Gain of catalytic residue at L93 (P = 0.1153);Gain of catalytic residue at L93 (P = 0.1153);
MVP		0.95
MPC		0.92
ClinPred		0.95	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs895822620; hg19: chr9-133333875;