rs773348232
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_001673.5(ASNS):c.1192_1193insT(p.Tyr398LeufsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
ASNS
NM_001673.5 frameshift
NM_001673.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.12
Genes affected
ASNS (HGNC:753): (asparagine synthetase (glutamine-hydrolyzing)) The protein encoded by this gene is involved in the synthesis of asparagine. This gene complements a mutation in the temperature-sensitive hamster mutant ts11, which blocks progression through the G1 phase of the cell cycle at nonpermissive temperature. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, May 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 7-97854625-T-TA is Pathogenic according to our data. Variant chr7-97854625-T-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 377228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASNS | NM_001673.5 | c.1192_1193insT | p.Tyr398LeufsTer4 | frameshift_variant | 10/13 | ENST00000394308.8 | |
CZ1P-ASNS | NR_147989.1 | n.2895_2896insT | non_coding_transcript_exon_variant | 16/19 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASNS | ENST00000394308.8 | c.1192_1193insT | p.Tyr398LeufsTer4 | frameshift_variant | 10/13 | 1 | NM_001673.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251420Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135874
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000205 AC: 3AN: 1461824Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727218
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Data not reliable, filtered out with message: AS_VQSR
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 10, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with ASNS-related conditions. ClinVar contains an entry for this variant (Variation ID: 377228). This variant is present in population databases (rs773348232, ExAC 0.001%). This sequence change creates a premature translational stop signal (p.Tyr398Leufs*4) in the ASNS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ASNS are known to be pathogenic (PMID: 27422383, 30057589). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Oct 14, 2016 | - - |
Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 02, 2021 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at