rs199422165
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_018136.5(ASPM):c.4795C>T(p.Arg1599Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,460,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as 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.4795C>T | p.Arg1599Ter | stop_gained | 18/28 | ENST00000367409.9 | |
ASPM | NM_001206846.2 | c.4066-8292C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASPM | ENST00000367409.9 | c.4795C>T | p.Arg1599Ter | stop_gained | 18/28 | 1 | NM_018136.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249524Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134944
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1460814Hom.: 0 Cov.: 38 AF XY: 0.00000826 AC XY: 6AN XY: 726720
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 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 28, 2018 | The R1599X nonsense variant in the ASPM gene has been reported previously as a homozygous pathogenic variant in several families with microcephaly (Bond et al., 2013; Tan et al., 2014). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Therefore, R1599X is interpreted to be a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 13, 2022 | This sequence change creates a premature translational stop signal (p.Arg1599*) 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 (rs199422165, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with clinical features of ASPM-related conditions (PMID: 14574646). ClinVar contains an entry for this variant (Variation ID: 21588). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at