rs28941472

Positions:

• chr7-66089114-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000048.4(ASL):​c.857A>G​(p.Gln286Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000911 in 1,613,784 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 Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: ASL NM_000048.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 7.26

Genes affected

ASL (HGNC:746): (argininosuccinate lyase) This gene encodes a member of the lyase 1 family. The encoded protein forms a cytosolic homotetramer and primarily catalyzes the reversible hydrolytic cleavage of argininosuccinate into arginine and fumarate, an essential step in the liver in detoxifying ammonia via the urea cycle. Mutations in this gene result in the autosomal recessive disorder argininosuccinic aciduria, or argininosuccinic acid lyase deficiency. A nontranscribed pseudogene is also located on the long arm of chromosome 22. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927
• PP5: Variant 7-66089114-A-G is Pathogenic according to our data. Variant chr7-66089114-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 2399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-66089114-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASL	NM_000048.4	c.857A>G	p.Gln286Arg	missense_variant	12/17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.857A>G	p.Gln286Arg	missense_variant	11/16		NP_001020114.1
ASL	NM_001024944.2	c.857A>G	p.Gln286Arg	missense_variant	11/15		NP_001020115.1
ASL	NM_001024946.2	c.779A>G	p.Gln260Arg	missense_variant	10/15		NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.857A>G	p.Gln286Arg	missense_variant	12/17	1	NM_000048.4	ENSP00000307188	P1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000120 AC: 30 AN: 250924 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135834

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000862 AC: 126 AN: 1461684 Hom.: 0 Cov.: 33 AF XY: 0.0000866 AC XY: 63 AN XY: 727166

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.000263

Gnomad4 NFE exome AF: 0.0000764

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152100 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74314

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.000189

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 286 of the ASL protein (p.Gln286Arg). This variant is present in population databases (rs28941472, gnomAD 0.02%). This missense change has been observed in individuals with argininosuccinate lyase deficiency (PMID: 12408190, 19703900, 21667091, 23430928). ClinVar contains an entry for this variant (Variation ID: 2399). 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 ASL protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ASL function (PMID: 9686346, 11747433, 19703900, 21667091). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 24, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 26, 2019	NM_001024943.1(ASL):c.857A>G(Q286R) is classified as pathogenic in the context of argininosuccinic aciduria. Sources cited for classification include the following: PMID 11747433, 24166829, 15273245, 9686346, 11747432, 19703900, 21667091 and 25778938. Classification of NM_001024943.1(ASL):c.857A>G(Q286R) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 07, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 03, 2016	Variant summary: The ASL c.857A>G (p.Gln286Arg) variant is indicated to located on the highly conserved and flexible loop C3 comprising residues 270-290 (called 280's loop) that has been proposed to be involved in entry of the substrate and exit of the product at the catalytic center (Balmer_2012) with 4/5 in silico tools predict a damaging outcome, which is further supported by functional studies, Trevisson_2009. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 9/120022 (1/13335), which does not exceed the estimated maximal expected allele frequency for a pathogenic ASL variant of 1/236. The variant of interest has been reported in multiple affected individuals, both as compound heterozygotes and homozygotes, via publications. In addition, multiple databases/clinical diagnostic laboratories have cited the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 30, 2017	Across a selection of the available literature, the ASL c.857A>G (p.Gln286Arg) missense variant has been identified in a total of 18 individuals with argininosuccinate lyase deficiency, including in nine individuals in a homozygous state, in seven individuals in a compound heterozygous state and in two affected individuals in a heterozygous state in whom a second variant was not identified (Walker et al. 1997; Linnebank et al. 2002; Balmer et al. 2014). In two of the compound heterozygotes the second variant results is a frameshift leading to early termination of the protein and in the remaining four compound heterozygotes it is a missense variant. In the study by Balmer et al. (2014), four of the homozygotes and two of the compound heterozygotes were noted to have neonatal onset of the disease with one of the compound heterozygotes noted to have late onset of the disease. The age of onset for the remaining four homozygotes and four compound heterozygotes was unknown. The variant has been noted to be associated with a severe phenotype (Balmer et al. 2014). The p.Gln286Arg variant was absent from 20 controls (Walker et al. 1997) and is reported at a frequency of 0.00047 in the other population of the Exome Aggregation Consortium. Sampaleanu et al. (2001) note that the Gln286 residue is located in a highly conserved and flexible loop region of the protein that has been proposed to be involved in entry of the substrate and exit of the product at the catalytic center. Substitution of the glutamine at this residue to arginine changes the interactions of this loop and neighbouring residues that may impact catalysis. Expression of the variant p.Gln286Arg protein in COS-1 cells and HEK293T cells resulted in a similar level of protein expression of the correct size compared to wild type (Walker et al. 1997; Hu et al. 2015). However, the variant protein was shown to retain no significant residual enzymatic activity in either patient-derived red blood cells (less than 5%) or fibroblasts (less than 3%) or when expressed in E.coli, COS-1 cells (0.05%), or HEK293T cells (Walker et al. 1997; Balmer et al. 2014; Hu et al. 2015). Based on the collective evidence, the p.Gln286Arg variant is classified as pathogenic for argininosuccinate lyase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 22, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2024	Reported many times in unrelated patients with argininosuccinic aciduria and has been identified on approximately 8% of ASL pathogenic alleles (PMID: 12384776); 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: 22231378, 12408190, 25778938, 11747433, 21667091, 24166829, 9686346, 30285816, 31943503, 17326097, 31980526, 34426522, 32778825, 31589614, 38198573, 36270249, 9045711, 12384776, 11747432) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;D;D;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H;.;H;.;H;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.9	D;D;D;D;D;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0040	D;D;D;D;D;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		0.61	P;.;P;.;.;.
Vest4		0.92
MVP		0.98
MPC		0.89
ClinPred		0.94	D
GERP RS		4.9
Varity_R		0.94
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28941472; hg19: chr7-65554101;