rs587783265
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_018136.5(ASPM):c.7160_7161delCT(p.Ser2387CysfsTer14) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000411 in 1,461,050 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_018136.5 frameshift
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ASPM | NM_018136.5 | c.7160_7161delCT | p.Ser2387CysfsTer14 | frameshift_variant | Exon 18 of 28 | ENST00000367409.9 | NP_060606.3 | |
ASPM | NM_001206846.2 | c.4066-5927_4066-5926delCT | intron_variant | Intron 17 of 26 | NP_001193775.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250328Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135250
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461050Hom.: 0 AF XY: 0.00000413 AC XY: 3AN XY: 726824
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Microcephaly 5, primary, autosomal recessive Pathogenic:2
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not provided Pathogenic:1
This sequence change creates a premature translational stop signal (p.Ser2387Cysfs*14) 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 (rs587783266, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ASPM-related conditions. ClinVar contains an entry for this variant (Variation ID: 157867). For these reasons, this variant has been classified as Pathogenic. -
Autosomal recessive primary microcephaly Pathogenic:1
Variant summary: ASPM c.7160_7161delCT (p.Ser2387CysfsX14) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 1.2e-05 in 250328 control chromosomes (gnomAD). To our knowledge, no occurrence of c.7160_7161delCT in individuals affected with Primary microcephaly and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
ASPM-related disorder Pathogenic:1
The ASPM c.7160_7161delCT variant is predicted to result in a frameshift and premature protein termination (p.Ser2387Cysfs*14). To our knowledge, this variant has not been reported in the literature. It is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. Frameshift variants in ASPM are expected to be pathogenic. This variant is interpreted as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at