rs199422194
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_018136.5(ASPM):c.9697C>T(p.Arg3233Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,460,386 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_018136.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASPM | NM_018136.5 | c.9697C>T | p.Arg3233Ter | stop_gained | 24/28 | ENST00000367409.9 | |
ASPM | NM_001206846.2 | c.4942C>T | p.Arg1648Ter | stop_gained | 23/27 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASPM | ENST00000367409.9 | c.9697C>T | p.Arg3233Ter | stop_gained | 24/28 | 1 | NM_018136.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000799 AC: 2AN: 250264Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135290
GnomAD4 exome AF: 0.00000822 AC: 12AN: 1460386Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 726536
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Microcephaly 5, primary, autosomal recessive Pathogenic:3Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Apr 18, 2022 | PVS1 PM2 - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 14, 2017 | The R3233X nonsense variant has been reported previously as a homozygous variant in multiple families with MCPH (Muhammad et al., 2009; Abdel-Hamid et al., 2016). The R3233X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2024 | This sequence change creates a premature translational stop signal (p.Arg3233*) in the ASPM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ASPM are known to be pathogenic (PMID: 19028728, 23611254). This variant is present in population databases (rs199422194, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with primary microcephaly (PMID: 19353628, 31934343). ClinVar contains an entry for this variant (Variation ID: 21634). For these reasons, this variant has been classified as Pathogenic. - |
See cases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jan 13, 2022 | ACMG classification criteria: PVS1, PM2 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at