rs367543005

Positions:

• chr7-66089693-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1 PM2 PP3 PP5_Very_Strong

The NM_000048.4(ASL):​c.1060C>T​(p.Gln354Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASL NM_000048.4 stop_gained, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 1.47

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 19 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-66089693-C-T is Pathogenic according to our data. Variant chr7-66089693-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 21253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-66089693-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASL	NM_000048.4	c.1060C>T	p.Gln354Ter	stop_gained, splice_region_variant	14/17	ENST00000304874.14
ASL	NM_001024943.2	c.1060C>T	p.Gln354Ter	stop_gained, splice_region_variant	13/16
ASL	NM_001024944.2	c.1000C>T	p.Gln334Ter	stop_gained, splice_region_variant	12/15
ASL	NM_001024946.2	c.982C>T	p.Gln328Ter	stop_gained, splice_region_variant	12/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASL	ENST00000304874.14	c.1060C>T	p.Gln354Ter	stop_gained, splice_region_variant	14/17	1	NM_000048.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00152 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 06, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 26, 2019	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 05, 2016	Variant summary: The c.1060C>T variant results in a premature termination codon, predicted to cause a truncated or absent ASL protein, which is a commonly known mechanism for disease. One in-silico tool predicts damaging outcome for this variant. 4/5 splice prediction tools predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions are not confirmed by experimental studies.This variant is not found in 116646 control chromosomes. This variant has been reported in many affected individuals as a founder mutation in the Saudi population (Al-Sayed_JIMD_2005). In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 22, 2021	- -
Pathogenic, criteria provided, single submitter	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 24, 2023	This sequence change creates a premature translational stop signal (p.Gln354*) in the ASL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ASL are known to be pathogenic (PMID: 2263616, 24166829). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with argininosuccinic aciduria (PMID: 16435180). ClinVar contains an entry for this variant (Variation ID: 21253). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 14, 2016	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2016	p.Q354* CAG>TAG c.1060C>T nonsense variant in the ASL gene was identified in the homozygous state in 14 of 28 patients from Saudi Arabia who were diagnosed with argininosuccinic aciduria (ASA) after being detected on MS/MS newborn screening (Al-Sayed et al., 2005). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 02, 2016	- -

ASL-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 03, 2024

The ASL c.1060C>T variant is predicted to result in premature protein termination (p.Gln354*). This variant was reported to be causative for argininosuccinic aciduria (Al-Sayed et al. 2005. PubMed ID: 16435180; AlTassan et al. 2018. PubMed ID: 29326055). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in ASL are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	51
DANN	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.78	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.89
ClinPred		1.0	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.73		Position offset: -2
DS_DL_spliceai		0.53		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs367543005; hg19: chr7-65554680;