rs869312990
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_000048.4(ASL):c.718+5G>A variant causes a splice donor 5th base, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
ASL
NM_000048.4 splice_donor_5th_base, intron
NM_000048.4 splice_donor_5th_base, intron
Scores
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.68
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 Likely_pathogenic. Variant got 7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 7-66087796-G-A is Pathogenic according to our data. Variant chr7-66087796-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 224975.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}. Variant chr7-66087796-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASL | NM_000048.4 | c.718+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000304874.14 | |||
ASL | NM_001024943.2 | c.718+5G>A | splice_donor_5th_base_variant, intron_variant | ||||
ASL | NM_001024944.2 | c.718+5G>A | splice_donor_5th_base_variant, intron_variant | ||||
ASL | NM_001024946.2 | c.640+5G>A | splice_donor_5th_base_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASL | ENST00000304874.14 | c.718+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_000048.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Argininosuccinate lyase deficiency Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 21, 2021 | 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. Studies have shown that this variant is associated with skipping of exon 9 but is expected to preserve the integrity of the reading frame (PMID: 12384776). This variant has been observed in an individual affected with argininosuccinate lyase deficiency (PMID: 12384776). This variant is also known as IVS9+5G>A. ClinVar contains an entry for this variant (Variation ID: 224975). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 10 of the ASL gene. It does not directly change the encoded amino acid sequence of the ASL protein, but it affects a nucleotide within the consensus splice site of the intron. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 01, 2018 | - - |
Pathogenic, criteria provided, single submitter | literature only | SNPedia | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at