rs398123126

Variant names:

• chr7-66086763-C-G
• rs398123126
• NM_000048.4:c.544C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-66086763-C-G
• chr7-66086763-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_000048.4(ASL):​c.544C>G​(p.Arg182Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,451,352 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R182Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ASL NM_000048.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 3.46
• Publications: 0 publications found

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]

ASL Gene-Disease associations (from GenCC):

• argininosuccinic aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 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_000048.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-66086764-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 203613.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, 0.961
• PP5: Variant 7-66086763-C-G is Pathogenic according to our data. Variant chr7-66086763-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2735029.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASL	NM_000048.4	c.544C>G	p.Arg182Gly	missense_variant	Exon 8 of 17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.544C>G	p.Arg182Gly	missense_variant	Exon 7 of 16		NP_001020114.1
ASL	NM_001024944.2	c.544C>G	p.Arg182Gly	missense_variant	Exon 7 of 15		NP_001020115.1
ASL	NM_001024946.2	c.524+101C>G		intron_variant	Intron 6 of 14		NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.544C>G	p.Arg182Gly	missense_variant	Exon 8 of 17	1	NM_000048.4	ENSP00000307188.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1451352 Hom.: 0 Cov.: 32 AF XY: 0.00000416 AC XY: 3 AN XY: 721352

African (AFR) AF: 0.00 AC: 0 AN: 33310

American (AMR) AF: 0.00 AC: 0 AN: 42834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25866

East Asian (EAS) AF: 0.00 AC: 0 AN: 39236

South Asian (SAS) AF: 0.00 AC: 0 AN: 85004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1107580

Other (OTH) AF: 0.00 AC: 0 AN: 59998

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:2

Apr 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts the p.Arg182 amino acid residue in ASL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19703900, 24166829; 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 glycine, which is neutral and non-polar, at codon 182 of the ASL protein (p.Arg182Gly). 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. -

May 01, 2025

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Uncertain:1

Mar 10, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ASL c.544C>G (p.Arg182Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 228134 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.544C>G has been reported in the literature in individuals affected with Argininosuccinic Aciduria with non informative genotype (example: Balmer_2013, and Al-Jasmi_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Argininosuccinic Aciduria. 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: 26589311, 24166829). ClinVar contains an entry for this variant (Variation ID: 2735029). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;D;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	.;D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;M;.;M
PhyloP100		3.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.8	D;D;D;D
REVEL	Pathogenic	0.98
Sift	Benign	0.14	T;T;T;T
Sift4G	Uncertain	0.053	T;T;D;T
Polyphen		1.0	D;D;.;.
Vest4		0.97
MutPred		0.82		Loss of MoRF binding (P = 0.0149);Loss of MoRF binding (P = 0.0149);.;Loss of MoRF binding (P = 0.0149);
MVP		0.98
MPC		1.0
ClinPred		0.96	D
GERP RS		3.7
Varity_R		0.96
gMVP		0.98
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs398123126; hg19: chr7-65551750;