rs28941473

Positions:

• chr7-66086751-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1 PM2 PP5_Very_Strong BP4

The NM_000048.4(ASL):​c.532G>A​(p.Val178Met) variant causes a missense change. The variant allele was found at a frequency of 0.000402 in 1,605,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: ASL NM_000048.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 5.90

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a helix (size 25) in uniprot entity ARLY_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000048.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-66086751-G-A is Pathogenic according to our data. Variant chr7-66086751-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-66086751-G-A is described in Lovd as [Pathogenic]. Variant chr7-66086751-G-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.21561202). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASL	NM_000048.4	c.532G>A	p.Val178Met	missense_variant	8/17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.532G>A	p.Val178Met	missense_variant	7/16		NP_001020114.1
ASL	NM_001024944.2	c.532G>A	p.Val178Met	missense_variant	7/15		NP_001020115.1
ASL	NM_001024946.2	c.524+89G>A		intron_variant			NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.532G>A	p.Val178Met	missense_variant	8/17	1	NM_000048.4	ENSP00000307188.9

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000294 AC: 68 AN: 231396 Hom.: 0 AF XY: 0.000286 AC XY: 36 AN XY: 125942

Gnomad AFR exome AF: 0.0000692

Gnomad AMR exome AF: 0.0000615

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000472

Gnomad NFE exome AF: 0.000502

Gnomad OTH exome AF: 0.000697

GnomAD4 exome AF: 0.000409 AC: 594 AN: 1453354 Hom.: 0 Cov.: 32 AF XY: 0.000364 AC XY: 263 AN XY: 722556

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000693

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000716

Gnomad4 NFE exome AF: 0.000474

Gnomad4 OTH exome AF: 0.000433

GnomAD4 genome AF: 0.000341 AC: 52 AN: 152272 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74446

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.000351

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000322 AC: 39

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 22, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 06, 2017	Variant summary: The ASL c.532G>A (p.Val178Met) variant located in the central core heliz bundle forming the tetramer (per Balmer_2012 PMID: 24166829) causes a missense change involving a conserved nucleotide, which 3/5 in silico tools predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 35/68898 (1/1968), which does not exceed the estimated maximal expected allele frequency for a pathogenic ASL variant of 1/236. Multiple publications have reported the variant in affected individuals, who were homozygous or compound heterozygous. Functional studyies showed variant with ASL activity about 5% of WT's . In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 178 of the ASL protein (p.Val178Met). This variant is present in population databases (rs28941473, gnomAD 0.07%). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 12408190, 17326097, 19703900, 20236848). ClinVar contains an entry for this variant (Variation ID: 2402). 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. Experimental studies have shown that this missense change affects ASL function (PMID: 19703900, 21667091, 25778938). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 26, 2019	NM_001024943.1(ASL):c.532G>A(V178M) is classified as pathogenic in the context of argininosuccinic aciduria. Sources cited for classification include the following: PMID 12408190, 21667091, 21667091 and 24166829. Classification of NM_001024943.1(ASL):c.532G>A(V178M) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2023	Published functional studies found this variant is associated with significantly reduced argininosuccinate lyase activity compared to wild-type (Engel et al., 2012; Doimo et al., 2012; Hu et al., 2015); This variant is associated with the following publications: (PMID: 28251416, 24166829, 17326097, 20236848, 34598035, 31589614, 22231378, 12384776, 19703900, 25778938, 31943503, 12408190, 31980526, 21667091) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 11, 2022	PP4, PM2, PM3, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 24, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2024

The c.532G>A (p.V178M) alteration is located in exon 8 (coding exon 7) of the ASL gene. This alteration results from a G to A substitution at nucleotide position 532, causing the valine (V) at amino acid position 178 to be replaced by a methionine (M). Based on data from gnomAD, the A allele has an overall frequency of 0.031% (82/262774) total alleles studied. The highest observed frequency was 0.052% (62/118978) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and in conjunction with other ASL variants in individuals with intellectual disability, aggression, hyperactivity, seizures, neonatal onset coma, and/or biochemical findings consistent with argininosuccinic aciduria; in at least one instance, the variants were identified in trans (Kleijer, 2002; Trevisson, 2007; Trevisson, 2009; Mercimek-Mahmutoglu, 2010; Baruteau, 2017). This amino acid position is highly conserved in available vertebrate species. In multiple assays testing ASL function, this variant showed functionally normal and functionally abnormal results (Trevisson 2009, Engel 2012, Hu 2015). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D;D;T;.
Eigen	Benign	0.0076
Eigen_PC	Benign	0.036
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	.;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.69	N;N;.;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.36	N;N;N;N
REVEL	Pathogenic	0.69
Sift	Benign	0.22	T;T;T;T
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.95	P;P;.;.
Vest4		0.84
MVP		0.84
MPC		0.45
ClinPred		0.039	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.89

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: rs28941473; hg19: chr7-65551738;