rs757109353

Positions:

• chr7-66092771-CCT-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000048.4(ASL):​c.1255_1256delCT​(p.Leu419fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000684 in 1,461,688 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: ASL NM_000048.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.19

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]

ENSG00000249319 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-66092771-CCT-C is Pathogenic according to our data. Variant chr7-66092771-CCT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555167.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.1255_1256delCT	p.Leu419fs	frameshift_variant	17/17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.1255_1256delCT	p.Leu419fs	frameshift_variant	16/16		NP_001020114.1
ASL	NM_001024944.2	c.1195_1196delCT	p.Leu399fs	frameshift_variant	15/15		NP_001020115.1
ASL	NM_001024946.2	c.1177_1178delCT	p.Leu393fs	frameshift_variant	15/15		NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.1255_1256delCT	p.Leu419fs	frameshift_variant	17/17	1	NM_000048.4	ENSP00000307188.9
ENSG00000249319	ENST00000450043.2	c.563+109_563+110delCT		intron_variant		5		ENSP00000396527.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250964 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135724

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461688 Hom.: 0 AF XY: 0.00000963 AC XY: 7 AN XY: 727160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 13, 2023	This sequence change results in a frameshift in the ASL gene (p.Leu419Valfs*54). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 46 amino acid(s) of the ASL protein and extend the protein by 7 additional amino acid residues. This variant is present in population databases (rs757109353, gnomAD 0.006%). This frameshift has been observed in individual(s) with ASL-related conditions (PMID: 24166829). ClinVar contains an entry for this variant (Variation ID: 555167). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ASL function (PMID: 31943503). This variant disrupts a region of the ASL protein in which other variant(s) (p.Trp450*) have been determined to be pathogenic (PMID: 17326097, 19703900, 24166829, 26843370). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 16, 2022	Variant summary: ASL c.1255_1256delCT (p.Leu419ValfsX54) causes a frameshift in the last exon that is not expected to cause nonsense mediated decay (NMD), but removes a part of the 464 amino acid long protein and replaces it with an incorrect sequence, resulting in an extension of the protein. This alteration eliminates a part of the C-terminal domain (amino acids 368-435; IPR029419). Truncating variants downstream from this position have been reported in affected individuals (HGMD). The variant allele was found at a frequency of 1.2e-05 in 250964 control chromosomes (gnomAD). This variant (or similar protein level truncations) has been reported in the literature in individuals affected with ASL deficiency (e.g. Balmer_2014, Zielonka_2020, Jin_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported for this variant in isolation. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 21, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 14, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 12, 2021	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 22, 2022

Frameshift variant predicted to result in protein elongation as the last 46 amino acids are replaced with 53 different amino acids, and another frameshift variant resulting in protein elongation has has been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24166829, 31943503) -

Computational scores

Source: dbNSFP v4.3

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: rs757109353; hg19: chr7-65557758;