rs28941473

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 11P and 1B. PM1PP2PP5_Very_StrongBP4

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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 5.90

Publications

17 publications found

Variant links:

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

ASL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000048.4

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.

PP5

Variant 7-66086751-G-A is Pathogenic according to our data. Variant chr7-66086751-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
ASL	NM_000048.4 link	c.532G>A	p.Val178Met	missense_variant	Exon 8 of 17	ENST00000304874.14	NP_000039.2	P04424-1A0A024RDL8
ASL	NM_001024943.2 link	c.532G>A	p.Val178Met	missense_variant	Exon 7 of 16		NP_001020114.1	P04424-1A0A024RDL8
ASL	NM_001024944.2 link	c.532G>A	p.Val178Met	missense_variant	Exon 7 of 15		NP_001020115.1	P04424-2
ASL	NM_001024946.2 link	c.524+89G>A		intron_variant	Intron 6 of 14		NP_001020117.1	A0A0S2Z316

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14 link	c.532G>A	p.Val178Met	missense_variant	Exon 8 of 17	1	NM_000048.4	ENSP00000307188.9		P04424-1

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000294

AC:

AN:

231396

AF XY:

0.000286

show subpopulations

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 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.:

Cov.:

AF XY:

0.000364

AC XY:

263

AN XY:

722556

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33342

American (AMR)

AF:

0.0000693

AC:

AN:

43300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25914

East Asian (EAS)

AF:

0.00

AC:

AN:

39370

South Asian (SAS)

AF:

0.00

AC:

AN:

85232

European-Finnish (FIN)

AF:

0.000716

AC:

AN:

51676

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.000474

AC:

526

AN:

1108684

Other (OTH)

AF:

0.000433

AC:

AN:

60084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

112

149

186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000341

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41550

American (AMR)

AF:

0.0000654

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000754

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000603

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000325

Hom.:

Bravo

AF:

0.000351

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000322

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:8

Jan 11, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP4, PM2, PM3, PS3, PS4 -

Feb 12, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 24, 2015

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ASL: PM3:Very Strong, PM2, PP3, PP4, PS3:Supporting -

Argininosuccinate lyase deficiency

Pathogenic:8

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Invitae Evidence 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 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. -

Sep 01, 2002

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 26, 2019

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 06, 2017

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Mar 30, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Inborn genetic diseases

Pathogenic:1

Sep 20, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

(source)

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

LIST_S2

Pathogenic

0.99

.;D;D;D

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.22

T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.69

N;N;.;N

PhyloP100

5.9

PrimateAI

Pathogenic

0.81

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

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.43

gMVP

0.89

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over