GeneBe

rs767271619

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_000048.4(ASL):​c.1367G>A​(p.Arg456Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,610,384 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 (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ASL
NM_000048.4 missense

Scores

7
7
5

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U:1

Conservation

PhyloP100: 7.75
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.81
PP5
Variant 7-66092884-G-A is Pathogenic according to our data. Variant chr7-66092884-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551210.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
ASLNM_000048.4 linkc.1367G>A p.Arg456Gln missense_variant Exon 17 of 17 ENST00000304874.14 NP_000039.2 P04424-1A0A024RDL8
ASLNM_001024943.2 linkc.1367G>A p.Arg456Gln missense_variant Exon 16 of 16 NP_001020114.1 P04424-1A0A024RDL8
ASLNM_001024944.2 linkc.1307G>A p.Arg436Gln missense_variant Exon 15 of 15 NP_001020115.1 P04424-2
ASLNM_001024946.2 linkc.1289G>A p.Arg430Gln missense_variant Exon 15 of 15 NP_001020117.1 A0A0S2Z316

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ASLENST00000304874.14 linkc.1367G>A p.Arg456Gln missense_variant Exon 17 of 17 1 NM_000048.4 ENSP00000307188.9 P04424-1
ENSG00000249319ENST00000450043.2 linkc.563+221G>A intron_variant Intron 7 of 11 5 ENSP00000396527.2 H7C0S8

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152224
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000447
AC:
11
AN:
246024
Hom.:
0
AF XY:
0.00000748
AC XY:
1
AN XY:
133672
show subpopulations
Gnomad AFR exome
AF:
0.0000631
Gnomad AMR exome
AF:
0.000290
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000117
AC:
17
AN:
1458160
Hom.:
0
Cov.:
32
AF XY:
0.00000551
AC XY:
4
AN XY:
725544
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000201
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:
0.00000720
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152224
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.0000482
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000563
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:5Uncertain:1
Jan 07, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 456 of the ASL protein (p.Arg456Gln). This variant is present in population databases (rs767271619, gnomAD 0.03%). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 24166829, 31943503). ClinVar contains an entry for this variant (Variation ID: 551210). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ASL protein function with a positive predictive value of 95%. This variant disrupts the p.Arg456 amino acid residue in ASL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17326097). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Mar 21, 2017
Counsyl
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: clinical testing

- -

Feb 23, 2023
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 30, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 20, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 18, 2023
Revvity Omics, Revvity
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Pathogenic
0.23
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.49
T;.;T;.
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.89
.;D;D;D
M_CAP
Pathogenic
0.93
D
MetaRNN
Pathogenic
0.81
D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.0
M;.;M;.
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-1.3
N;N;N;N
REVEL
Pathogenic
0.88
Sift
Benign
0.054
T;T;T;T
Sift4G
Benign
0.084
T;T;T;T
Polyphen
0.98
D;.;D;.
Vest4
0.54
MutPred
0.48
Loss of MoRF binding (P = 0.0103);.;Loss of MoRF binding (P = 0.0103);.;
MVP
0.96
MPC
0.34
ClinPred
0.14
T
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.32
gMVP
0.71

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.33
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.33
Position offset: 28

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs767271619; hg19: chr7-65557871; API