rs781331391
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_000048.4(ASL):c.918+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000048 in 1,459,392 control chromosomes in the GnomAD database, with no homozygous occurrence. 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
Consequence
NM_000048.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ASL | NM_000048.4 | c.918+5G>A | splice_region_variant, intron_variant | Intron 12 of 16 | ENST00000304874.14 | NP_000039.2 | ||
ASL | NM_001024943.2 | c.918+5G>A | splice_region_variant, intron_variant | Intron 11 of 15 | NP_001020114.1 | |||
ASL | NM_001024944.2 | c.918+5G>A | splice_region_variant, intron_variant | Intron 11 of 14 | NP_001020115.1 | |||
ASL | NM_001024946.2 | c.840+5G>A | splice_region_variant, intron_variant | Intron 10 of 14 | NP_001020117.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ASL | ENST00000304874.14 | c.918+5G>A | splice_region_variant, intron_variant | Intron 12 of 16 | 1 | NM_000048.4 | ENSP00000307188.9 | |||
ENSG00000249319 | ENST00000450043.2 | c.231+5G>A | splice_region_variant, intron_variant | Intron 3 of 11 | 5 | ENSP00000396527.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249232Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135478
GnomAD4 exome AF: 0.00000480 AC: 7AN: 1459392Hom.: 0 Cov.: 35 AF XY: 0.00000689 AC XY: 5AN XY: 726126
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Argininosuccinate lyase deficiency Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 03, 2023 | This sequence change falls in intron 12 of the ASL gene. It does not directly change the encoded amino acid sequence of the ASL protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs781331391, gnomAD 0.01%). This variant has been observed in individual(s) with clinical features of argininosuccinate lyase deficiency (PMID: 24166829; 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: 554215). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Sep 29, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at