rs143508372

Positions:

• chr7-66086790-C-G
• chr7-66086790-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_000048.4(ASL):​c.571C>G​(p.Arg191Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,438,498 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R191W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ASL NM_000048.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 1.78

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 15 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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 chr7-66086790-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445881.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Uncertain_significance=2, Likely_pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801
• PP5: Variant 7-66086790-C-G is Pathogenic according to our data. Variant chr7-66086790-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 692055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASL	NM_000048.4	c.571C>G	p.Arg191Gly	missense_variant	8/17	ENST00000304874.14
ASL	NM_001024943.2	c.571C>G	p.Arg191Gly	missense_variant	7/16
ASL	NM_001024944.2	c.571C>G	p.Arg191Gly	missense_variant	7/15
ASL	NM_001024946.2	c.524+128C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASL	ENST00000304874.14	c.571C>G	p.Arg191Gly	missense_variant	8/17	1	NM_000048.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000482 AC: 1 AN: 207286 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 112280

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000638

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1438498 Hom.: 0 Cov.: 32 AF XY: 0.00000280 AC XY: 2 AN XY: 713754

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000518

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.08e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:2 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 17, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 191 of the ASL protein (p.Arg191Gly). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of ASL-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 692055). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ASL protein function. This variant disrupts the p.Arg191 amino acid residue in ASL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21744316, 24166829, 31943503). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Oct 12, 2018	This variant has not been previously reported or functionally characterized in the literature to our knowledge. However, a variant involving the same amino acid but resulting in a different missense change (p.Arg191Trp) has been previously reported in an asymptomatic patient with argininosuccinate lyase deficiency detected by newborn screening (PMID: 24166829). The c.571C>G (p.Arg191Gly) variant detected in this individual is present in the heterozygous state in the gnomAD population database at a frequency of 0.0005% (1/201720) and thus is presumed to be rare. Based on the available evidence, the c.571C>G p.Arg191Gly variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;D;D;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Pathogenic	2.9	M;M;.;M
MutationTaster	Benign	0.69	D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.8	D;D;D;D
REVEL	Pathogenic	0.76
Sift	Benign	0.33	T;T;T;T
Sift4G	Benign	0.33	T;T;T;T
Polyphen		0.81	P;P;.;.
Vest4		0.46
MutPred		0.66		Loss of methylation at R191 (P = 0.0419);Loss of methylation at R191 (P = 0.0419);.;Loss of methylation at R191 (P = 0.0419);
MVP		0.97
MPC		0.69
ClinPred		0.87	D
GERP RS		3.6
Varity_R		0.58
gMVP		0.72

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: rs143508372; hg19: chr7-65551777;