1-197089991-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP3
The NM_018136.5(ASPM):c.9923G>A(p.Arg3308His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,092 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3308L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_018136.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASPM | NM_018136.5 | c.9923G>A | p.Arg3308His | missense_variant | 25/28 | ENST00000367409.9 | |
ASPM | NM_001206846.2 | c.5168G>A | p.Arg1723His | missense_variant | 24/27 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASPM | ENST00000367409.9 | c.9923G>A | p.Arg3308His | missense_variant | 25/28 | 1 | NM_018136.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151790Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250508Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135398
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461186Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726910
GnomAD4 genome ? AF: 0.0000395 AC: 6AN: 151906Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74208
ClinVar
Submissions by phenotype
Microcephaly 5, primary, autosomal recessive Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 19, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 157920). This missense change has been observed in individual(s) with clinical features of primary microcephaly (PMID: 23611254). This variant is present in population databases (rs201362977, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 3308 of the ASPM protein (p.Arg3308His). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at