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rs142637046

chr7-66083175-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong

The NM_000048.4(ASL):c.446+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000912 in 1,612,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

ASL
NM_000048.4 splice_donor

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 8.85
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 16 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.06953405 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.5, offset of 36, new splice context is: gagGTgtga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 7-66083175-G-A is Pathogenic according to our data. Variant chr7-66083175-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 92361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-66083175-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ASLNM_000048.4 linkuse as main transcriptc.446+1G>A splice_donor_variant ENST00000304874.14
ASLNM_001024943.2 linkuse as main transcriptc.446+1G>A splice_donor_variant
ASLNM_001024944.2 linkuse as main transcriptc.446+1G>A splice_donor_variant
ASLNM_001024946.2 linkuse as main transcriptc.446+1G>A splice_donor_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ASLENST00000304874.14 linkuse as main transcriptc.446+1G>A splice_donor_variant 1 NM_000048.4 P1P04424-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000790
AC:
12
AN:
151984
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
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:
0.00316
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000441
AC:
11
AN:
249560
Hom.:
0
AF XY:
0.0000665
AC XY:
9
AN XY:
135250
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.0000999
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.0000467
Gnomad NFE exome
AF:
0.0000712
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000925
AC:
135
AN:
1460040
Hom.:
0
Cov.:
31
AF XY:
0.0000964
AC XY:
70
AN XY:
726306
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000112
Gnomad4 OTH exome
AF:
0.0000830
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000789
AC:
12
AN:
152102
Hom.:
0
Cov.:
32
AF XY:
0.0000941
AC XY:
7
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000100
Hom.:
0
Bravo
AF:
0.0000453
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
?
    Exome Aggregation Consortium database
AF:
0.0000494
AC:
6
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:10
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsSep 09, 2023- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesAug 24, 2023The ASL c.446+1G>A variant (rs142637046) is reported in the literature in many individuals with argininosuccinic aciduria (Linnebank 2002, Toquet 2021). This variant is reported in ClinVar (Variation ID: 92361) and is found in the general population with an overall allele frequency of 0.005% (13/280,896 alleles) in the Genome Aggregation Database (v2.1.1). This variant disrupts the canonical splice donor site of intron 6, and experimental evidence found this variant results in the skipping of exon 5 (Linnebank 2002). Based on available information, this variant is considered to be pathogenic. References: Linnebank M et al. Argininosuccinate lyase (ASL) deficiency: mutation analysis in 27 patients and a completed structure of the human ASL gene. Hum Genet. 2002 Oct;111(4-5):350-9. PMID: 12384776. Toquet S et al. Adult-onset diagnosis of urea cycle disorders: Results of a French cohort of 71 patients. J Inherit Metab Dis. 2021 Sep;44(5):1199-1214. PMID: 34014557. -
Pathogenic, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, University Medical Center UtrechtJul 28, 2017- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Pathogenic, criteria provided, single submitterclinical testing3billionMay 22, 2022The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000092361). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 05, 2017Variant summary: The ASL c.446+1G>A variant involves the alteration of a conserved intronic nucleotide that 5/5 splice prediction tools predict a significant impact on splicing, which is supported by a functional study, Linnebank_2002. This variant was found in 6/117678 control chromosomes at a frequency of 0.000051, which does not exceed the estimated maximal expected allele frequency of a pathogenic ASL variant (0.0042258). The variant of interest (legacy name IVS5+1G>A) has been reported in multiple affected individuals as both compound heterozygotes and homozygotes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Nov 10, 2021NM_001024943.1(ASL):c.446+1G>A is a canonical splice variant classified as pathogenic in the context of argininosuccinic aciduria. c.446+1G>A has been observed in cases with relevant disease (PMID: 12384776). Functional assessments of this variant are available in the literature (PMID: 12384776). c.446+1G>A has been observed in population frequency databases (gnomAD: NFE <0.001%). In summary, NM_001024943.1(ASL):c.446+1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterMar 10, 2022- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 18, 2024This sequence change affects a donor splice site in intron 6 of the ASL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ASL are known to be pathogenic (PMID: 2263616, 24166829). This variant is present in population databases (rs142637046, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with argininosuccinate lyase (ASL) deficiency (PMID: 12384776). This variant is also known as IVS5+1G>A. ClinVar contains an entry for this variant (Variation ID: 92361). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 01, 2002- -
not provided Pathogenic:5
Pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 08, 2021Canonical splice site variant predicted to result in a null allele and deletion of the upstream exon in a gene for which loss-of-function is a known mechanism of disease (Linnebank et al., 2002); Identified in a patient with late onset argininosuccinic aciduria who also harbored a second ASL variant (Baruteau et al., 2017); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25087612, 25525159, 24166829, 12384776, 28251416, 31589614) -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 22, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.49
D
BayesDel_noAF
Pathogenic
0.30
Cadd
Pathogenic
33
Dann
Uncertain
0.99
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.98
D
MutationTaster
Benign
1.0
D;D;D;D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.84
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.84
Position offset: -1

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: rs142637046; hg19: chr7-65548162; API