rs28941472

Variant names:

• chr7-66089114-A-C
• NM_000048.4:c.857A>C

Your query was ambiguous. Multiple possible variants found:

• chr7-66089114-A-C
• chr7-66089114-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_000048.4(ASL):​c.857A>C​(p.Gln286Pro) variant causes a missense change involving the alteration of a 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. Q286R) has been classified as 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: 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]

ENSG00000249319 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-66089114-A-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 7-66089114-A-C is Pathogenic according to our data. Variant chr7-66089114-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2731175.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.857A>C	p.Gln286Pro	missense_variant	Exon 12 of 17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.857A>C	p.Gln286Pro	missense_variant	Exon 11 of 16		NP_001020114.1
ASL	NM_001024944.2	c.857A>C	p.Gln286Pro	missense_variant	Exon 11 of 15		NP_001020115.1
ASL	NM_001024946.2	c.779A>C	p.Gln260Pro	missense_variant	Exon 10 of 15		NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.857A>C	p.Gln286Pro	missense_variant	Exon 12 of 17	1	NM_000048.4	ENSP00000307188.9
ENSG00000249319	ENST00000450043.2	c.170A>C	p.Gln57Pro	missense_variant	Exon 3 of 12	5		ENSP00000396527.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Nov 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts the p.Gln286 amino acid residue in ASL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12408190, 19703900, 21667091, 23430928). 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 variant has not been reported in the literature in individuals affected with ASL-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 286 of the ASL protein (p.Gln286Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;D;D;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;.;H;.;H;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.8	D;D;D;D;D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		0.88	P;.;P;.;.;.
Vest4		0.87
MutPred		0.79		Gain of glycosylation at Q286 (P = 0.0056);.;Gain of glycosylation at Q286 (P = 0.0056);.;Gain of glycosylation at Q286 (P = 0.0056);.;
MVP		0.99
MPC		0.99
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.94

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-65554101;