chr7-66087368-C-T

Position:

• chr7-66087368-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000048.4(ASL):​c.637C>T​(p.Arg213*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,454,716 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: ASL NM_000048.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 2.61

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 18 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
• PP5: Variant 7-66087368-C-T is Pathogenic according to our data. Variant chr7-66087368-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 426366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASL	NM_000048.4	c.637C>T	p.Arg213*	stop_gained	9/17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.637C>T	p.Arg213*	stop_gained	8/16		NP_001020114.1
ASL	NM_001024944.2	c.637C>T	p.Arg213*	stop_gained	8/15		NP_001020115.1
ASL	NM_001024946.2	c.559C>T	p.Arg187*	stop_gained	7/15		NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.637C>T	p.Arg213*	stop_gained	9/17	1	NM_000048.4	ENSP00000307188.9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000204 AC: 5 AN: 245196 Hom.: 0 AF XY: 0.0000300 AC XY: 4 AN XY: 133254

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1454716 Hom.: 0 Cov.: 35 AF XY: 0.0000124 AC XY: 9 AN XY: 724014

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0000216

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 15, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 13, 2023	This sequence change creates a premature translational stop signal (p.Arg213*) 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 present in population databases (rs761651320, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 17326097, 30285816, 31183366). ClinVar contains an entry for this variant (Variation ID: 426366). 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 03, 2017	Variant summary: The ASL c.637C>T (p.Arg213X) variant results in a premature termination codon, predicted to cause a truncated or absent ASL protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 1/118802 control chromosomes at a frequency of 0.0000084, which does not exceed the estimated maximal expected allele frequency of a pathogenic ASL variant (0.0042258). Multiple publications have cited the variant in affected compound heterozygotes and homozygote individuals. In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 13, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 16, 2021	The ASL c.637C>T (p.Arg213Ter) variant is a stop-gained variant that is predicted to result in a premature termination or absence of the protein. The p.Arg213Ter variant is reported in at least eight individuals with argininosuccinate lyase deficiency, including in a homozygous state in one individual and in a compound heterozygous state, most often with a missense variant, in at least seven individuals (Trevisson et al. 2007; Balmer et al. 2014; Bijarnia-Mahay et al. 2018; Zhao et al. 2019; Zhang et al. 2021; Kido et al. 2021). Commonly reported phenotypic features in these individuals included hyperammonemia, elevated argininosuccinic acid, intellectual disability, epilepsy, and hepatic disease. The p.Arg213Ter variant is reported at a frequency of 0.000163 in the South Asian population of the Genome Aggregation Database (version 2.1.1). Transfection of the ASL p.Arg213Ter variant into HEK293T cells resulted in a significantly reduced enzyme activity as compared to cells transfected with the wild type protein (Zhao et al. 2019). Based on the available evidence, the p.Arg213Ter variant is classified as pathogenic for argininosuccinate lyase deficiency. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2018	The R213X variant has been reported previously in association with argininosuccinic aciduria (Trevisson et al. 2007). The R213X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R213X variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret this variant as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 30, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.79	D
Vest4		0.97
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.24		Position offset: 18

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

Publications

LitVar

Other links and lift over

dbSNP: rs761651320; hg19: chr7-65552355;