rs1449589636

chr7-66087369-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000048.4(ASL):c.638G>A(p.Arg213Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000436 in 1,606,744 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. R213P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ASL NM_000048.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 8.04

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 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr7-66087369-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3011645.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 7-66087369-G-A is Pathogenic according to our data. Variant chr7-66087369-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 558682.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.638G>A	p.Arg213Gln	missense_variant	9/17	ENST00000304874.14
ASL	NM_001024943.2	c.638G>A	p.Arg213Gln	missense_variant	8/16
ASL	NM_001024944.2	c.638G>A	p.Arg213Gln	missense_variant	8/15
ASL	NM_001024946.2	c.560G>A	p.Arg187Gln	missense_variant	7/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASL	ENST00000304874.14	c.638G>A	p.Arg213Gln	missense_variant	9/17	1	NM_000048.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151900 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454844 Hom.: 0 Cov.: 35 AF XY: 0.00000276 AC XY: 2 AN XY: 724072

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151900 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74186

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 16, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 23, 2023	Variant summary: ASL c.638G>A (p.Arg213Gln) results in a conservative amino acid change to a highly conserved residue (HGMD) located in the Fumarate lyase, N-terminal (IPR022761) of 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 245196 control chromosomes (gnomAD). c.638G>A has been reported in the literature in multiple individuals affected with Argininosuccinic Aciduria (Ali_2019, Balmer_2014), and one was reported as compound heterozygous with another pathogenic variant. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 31709144, 24166829). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic (n=2) or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Uncertain significance, flagged submission	clinical testing	Counsyl	Jun 04, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 18, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 213 of the ASL protein (p.Arg213Gln). For these reasons, this variant has been classified as 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. ClinVar contains an entry for this variant (Variation ID: 558682). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 24166829, 31709144; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.01%). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 09, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24166829, 31709144) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;D;D;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M;.;M;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.9	D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.023	D;D;D;D;D
Polyphen		0.99	D;.;D;.;.
Vest4		0.94
MutPred		0.80		Gain of catalytic residue at E214 (P = 0.3867);.;Gain of catalytic residue at E214 (P = 0.3867);.;Gain of catalytic residue at E214 (P = 0.3867);
MVP		0.97
MPC		0.83
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.95
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1449589636; hg19: chr7-65552356; COSMIC: COSV59189008; COSMIC: COSV59189008;