rs374304304

Variant names:

• chr7-66082440-C-A
• rs374304304
• NM_000048.4:c.280C>A

Your query was ambiguous. Multiple possible variants found:

• chr7-66082440-C-A
• chr7-66082440-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_000048.4(ASL):​c.280C>A​(p.Arg94Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R94H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASL NM_000048.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.96

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

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_000048.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-66082440-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 92359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 95 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 0.7488 (below the threshold of 3.09). Trascript score misZ: 1.388 (below the threshold of 3.09). GenCC associations: The gene is linked to argininosuccinic aciduria.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89
• PP5: Variant 7-66082440-C-A is Pathogenic according to our data. Variant chr7-66082440-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2829866.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASL	NM_000048.4	c.280C>A	p.Arg94Ser	missense_variant	Exon 4 of 17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.280C>A	p.Arg94Ser	missense_variant	Exon 3 of 16		NP_001020114.1
ASL	NM_001024944.2	c.280C>A	p.Arg94Ser	missense_variant	Exon 3 of 15		NP_001020115.1
ASL	NM_001024946.2	c.280C>A	p.Arg94Ser	missense_variant	Exon 3 of 15		NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.280C>A	p.Arg94Ser	missense_variant	Exon 4 of 17	1	NM_000048.4	ENSP00000307188.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:1

Jan 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts the p.Arg94 amino acid residue in ASL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24166829, 26745957; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 94 of the ASL protein (p.Arg94Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ASL-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;D;D;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.3	L;L;L;.;L
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.7	D;D;D;D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;T;D
Polyphen		1.0	D;.;D;.;.
Vest4		0.82
MutPred		0.60		Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);.;Gain of helix (P = 0.0496);
MVP		0.99
MPC		0.99
ClinPred		1.0	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.87
Mutation Taster		=2/98	disease causing

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: rs374304304; hg19: chr7-65547427;