rs763909256
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_018136.5(ASPM):c.8266C>T(p.Gln2756*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,600 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 (★★). 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ASPM | NM_018136.5 | c.8266C>T | p.Gln2756* | stop_gained | 18/28 | ENST00000367409.9 | NP_060606.3 | |
ASPM | NM_001206846.2 | c.4066-4821C>T | intron_variant | NP_001193775.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ASPM | ENST00000367409.9 | c.8266C>T | p.Gln2756* | stop_gained | 18/28 | 1 | NM_018136.5 | ENSP00000356379.4 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 1AN: 151604Hom.: 0 Cov.: 32 FAILED QC
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249576Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134990
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460600Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726622
GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000660 AC: 1AN: 151604Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74008
ClinVar
Submissions by phenotype
Microcephaly 5, primary, autosomal recessive Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 04, 2022 | The homozygous p.Gln2756Ter variant in ASPM was identified by our study in 2 siblings with autosomal recessive primary microcephaly 5. The variant has not been previously reported in individuals with autosomal recessive primary microcephaly 5, and has been identified in 1 individual by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs763909256). This variant has been reported in ClinVar (Variation ID: 522990) as pathogenic by Genomic Research Center, Shahid Beheshti University of Medical Sciences. This nonsense variant leads to a premature termination codon at position 2756, which is predicted to lead to a truncated or absent protein. Loss of function of the ASPM gene is an established disease mechanism in autosomal recessive primary microcephaly 5. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive primary microcephaly 5 based on the predicted impact of the variant, its absence from control populations, and its homozygous occurrence in affected individuals. ACMG/AMP Criteria applied: PVS1, PM3_supporting, PM2 (Richards 2015). - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 18, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 18, 2019 | DNA sequence analysis of the ASPM gene demonstrated a sequence change, c.8266C>T, which results in the creation of a premature stop codon at amino acid position 2756, p.Gln2756*, in the apparent homozygous state. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ASPM protein with potentially abnormal function. This pathogenic sequence change has not been reported in the literature and it is present in the gnomAD database with a low population frequency of 0.00041% (dbSNP NA). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at