rs587783211
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_018136.5(ASPM):c.10168C>T(p.Arg3390Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,606,934 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 Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
ASPM
NM_018136.5 stop_gained
NM_018136.5 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 3.31
Genes affected
ASPM (HGNC:19048): (assembly factor for spindle microtubules) This gene is the human ortholog of the Drosophila melanogaster 'abnormal spindle' gene (asp), which is essential for normal mitotic spindle function in embryonic neuroblasts. Studies in mouse also suggest a role of this gene in mitotic spindle regulation, with a preferential role in regulating neurogenesis. Mutations in this gene are associated with microcephaly primary type 5. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0255 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-197086966-G-A is Pathogenic according to our data. Variant chr1-197086966-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 157773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197086966-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASPM | NM_018136.5 | c.10168C>T | p.Arg3390Ter | stop_gained | 27/28 | ENST00000367409.9 | |
ASPM | NM_001206846.2 | c.5413C>T | p.Arg1805Ter | stop_gained | 26/27 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASPM | ENST00000367409.9 | c.10168C>T | p.Arg3390Ter | stop_gained | 27/28 | 1 | NM_018136.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 151920Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000203 AC: 5AN: 246548Hom.: 0 AF XY: 0.0000225 AC XY: 3AN XY: 133560
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GnomAD4 exome AF: 0.0000110 AC: 16AN: 1455014Hom.: 0 Cov.: 32 AF XY: 0.00000829 AC XY: 6AN XY: 724048
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Microcephaly 5, primary, autosomal recessive Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 17, 2013 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) | Apr 01, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 18, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 03, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with primary microcephaly (PMID: 25786579, 27250695). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 157773). This variant is present in population databases (rs587783211, ExAC 0.01%). This sequence change creates a premature translational stop signal (p.Arg3390*) 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). - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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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