rs1554328459

Variant names:

• chr7-66092814-A-C
• rs1554328459
• NM_000048.4:c.1297A>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000048.4(ASL):​c.1297A>C​(p.Ser433Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,522 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S433S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ASL NM_000048.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 7.97
• Publications: 1 publications found

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

ENSG00000249319 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899
• PP5: Variant 7-66092814-A-C is Pathogenic according to our data. Variant chr7-66092814-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 203621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASL	NM_000048.4	c.1297A>C	p.Ser433Arg	missense_variant	Exon 17 of 17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.1297A>C	p.Ser433Arg	missense_variant	Exon 16 of 16		NP_001020114.1
ASL	NM_001024944.2	c.1237A>C	p.Ser413Arg	missense_variant	Exon 15 of 15		NP_001020115.1
ASL	NM_001024946.2	c.1219A>C	p.Ser407Arg	missense_variant	Exon 15 of 15		NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.1297A>C	p.Ser433Arg	missense_variant	Exon 17 of 17	1	NM_000048.4	ENSP00000307188.9
ENSG00000249319	ENST00000450043.2	c.563+151A>C		intron_variant	Intron 7 of 11	5		ENSP00000396527.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461522 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727086

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111970

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000615 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:2 Uncertain:1

Oct 13, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Apr 13, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 433 of the ASL protein (p.Ser433Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 24166829, 30285816). ClinVar contains an entry for this variant (Variation ID: 203621). 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) performed at Invitae indicates that this missense variant is expected to disrupt ASL protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	.;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;.;H;.
PhyloP100		8.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.5	D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.91
MutPred		0.52		Gain of catalytic residue at S433 (P = 0.0497);.;Gain of catalytic residue at S433 (P = 0.0497);.;
MVP		0.99
MPC		0.99
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.94
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs1554328459; hg19: chr7-65557801;