rs746120802

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000048.4(ASL):​c.1154G>A​(p.Arg385His) variant causes a missense change. The variant allele was found at a frequency of 0.0000151 in 1,457,082 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. R385L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

ASL
NM_000048.4 missense

Scores

16
2
1

Clinical Significance

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

Conservation

PhyloP100: 5.39
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.955
PP5
Variant 7-66092567-G-A is Pathogenic according to our data. Variant chr7-66092567-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 552287.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
ASLNM_000048.4 linkuse as main transcriptc.1154G>A p.Arg385His missense_variant 16/17 ENST00000304874.14 NP_000039.2 P04424-1A0A024RDL8
ASLNM_001024943.2 linkuse as main transcriptc.1154G>A p.Arg385His missense_variant 15/16 NP_001020114.1 P04424-1A0A024RDL8
ASLNM_001024944.2 linkuse as main transcriptc.1094G>A p.Arg365His missense_variant 14/15 NP_001020115.1 P04424-2
ASLNM_001024946.2 linkuse as main transcriptc.1076G>A p.Arg359His missense_variant 14/15 NP_001020117.1 A0A0S2Z316

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ASLENST00000304874.14 linkuse as main transcriptc.1154G>A p.Arg385His missense_variant 16/171 NM_000048.4 ENSP00000307188.9 P04424-1
ENSG00000249319ENST00000450043.2 linkuse as main transcriptc.467G>A p.Arg156His missense_variant 7/125 ENSP00000396527.2 H7C0S8

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000121
AC:
3
AN:
247896
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134470
show subpopulations
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000266
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000151
AC:
22
AN:
1457082
Hom.:
0
Cov.:
32
AF XY:
0.0000110
AC XY:
8
AN XY:
725024
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.0000198
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000896
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

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
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsSep 04, 2023- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 28, 2023This variant is present in population databases (rs746120802, gnomAD 0.003%). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg385 amino acid residue in ASL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12408190, 18616627, 21667091, 25778938, 26745957). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 552287). This missense change has been observed in individuals with argininosuccinate lyase deficiency (PMID: 24166829, 31943503; Invitae). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 385 of the ASL protein (p.Arg385His). -
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterMay 15, 2023Criteria applied: PS3_MOD,PM3,PM5,PP4_MOD,PM2_SUP,PP3 -
Uncertain significance, flagged submissionclinical testingCounsylJun 02, 2017- -
Likely pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 06, 2023Variant summary: ASL c.1154G>A (p.Arg385His) results in a non-conservative amino acid change located in the Argininosuccinate lyase, C-terminal domain (IPR029419) of 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 1.2e-05 in 247896 control chromosomes (gnomAD). c.1154G>A has been reported in the literature in individuals affected with Argininosuccinic Aciduria (example: Balmer_2014 and Zielonka_2020). These data indicate that the variant may be associated with disease. A different amino acid change affecting the same residue (c.1154G>T/p.Arg385Leu) has been reported in individuals affected with Argininosuccinic Aciduria in homozygous state (Balmer_2014). This data suggests that this residue is critical for normal protein function. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and pathogenic/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, no assertion criteria providedclinical testingNatera, Inc.Nov 02, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.63
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.51
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.98
D;.;D;.;.
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
1.0
.;D;D;D;D
M_CAP
Pathogenic
0.95
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.0
H;.;H;.;.
PrimateAI
Uncertain
0.76
T
PROVEAN
Pathogenic
-4.8
D;D;D;D;.
REVEL
Pathogenic
0.99
Sift
Pathogenic
0.0
D;D;D;D;.
Sift4G
Pathogenic
0.0
D;D;D;D;D
Polyphen
1.0
D;.;D;.;.
Vest4
0.96
MVP
0.99
MPC
1.0
ClinPred
1.0
D
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.96
gMVP
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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

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

Other links and lift over

dbSNP: rs746120802; hg19: chr7-65557554; API