7-66092078-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000048.4(ASL):c.1135C>T(p.Arg379Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000589 in 1,612,042 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R379G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: ASL NM_000048.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.29

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 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000048.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-66092078-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2196834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 7-66092078-C-T is Pathogenic according to our data. Variant chr7-66092078-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-66092078-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASL	NM_000048.4	c.1135C>T	p.Arg379Cys	missense_variant	15/17	ENST00000304874.14
ASL	NM_001024943.2	c.1135C>T	p.Arg379Cys	missense_variant	14/16
ASL	NM_001024944.2	c.1075C>T	p.Arg359Cys	missense_variant	13/15
ASL	NM_001024946.2	c.1057C>T	p.Arg353Cys	missense_variant	13/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASL	ENST00000304874.14	c.1135C>T	p.Arg379Cys	missense_variant	15/17	1	NM_000048.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152056 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000642 AC: 16 AN: 249176 Hom.: 0 AF XY: 0.0000519 AC XY: 7 AN XY: 134846

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000562 AC: 82 AN: 1459986 Hom.: 0 Cov.: 32 AF XY: 0.0000661 AC XY: 48 AN XY: 726364

Gnomad4 AFR exome AF: 0.0000597

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: 0.0000194

Gnomad4 NFE exome AF: 0.0000585

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152056 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74270

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2020	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 09, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 09, 2022	Variant summary: ASL c.1135C>T (p.Arg379Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 249176 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ASL causing Argininosuccinic Aciduria (6.4e-05 vs 0.0042), allowing no conclusion about variant significance. c.1135C>T has been reported in the literature in homozygous and compound heterozygous individuals affected with Argininosuccinic Aciduria (Balmer_2014, Kleijer_2002, Mercimek-Mahmutoglu_2010). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant affects the enzyme stability and results in decreased enzyme activity (Kleijer_2002, Engel_2012, Hu_2015). Six laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 379 of the ASL protein (p.Arg379Cys). This variant is present in population databases (rs28940287, gnomAD 0.01%). This missense change has been observed in individual(s) with argininosuccinic aciduria (PMID: 12408190, 20236848, 27515243; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2403). 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%. Experimental studies have shown that this missense change affects ASL function (PMID: 21667091, 25778938). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 22, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2021	Published functional studies demonstrate that R379C is predicted to affect the stability of the argininosuccinate lyase enzyme and is associated with 10% of wild-type argininosuccinate lyase activity (Hu et al., 2015; Engel et al., 2012); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31943503, 31589614, 32152836, 20236848, 12408190, 27515243, 28643139, 26745957, 24166829, 12384776, 25778938, 21667091, 25087612) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;.;D;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M;.;M;.;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.6	D;D;D;D;.
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D;D;.
Sift4G	Uncertain	0.012	D;D;D;D;D
Polyphen		1.0	D;.;D;.;.
Vest4		0.92
MVP		0.98
MPC		1.0
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.76

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: rs28940287; hg19: chr7-65557065; COSMIC: COSV104538993; COSMIC: COSV104538993;