rs199422195
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_018136.5(ASPM):c.9730C>T(p.Arg3244Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,808 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 | UniProt |
---|---|---|---|---|---|---|---|
ASPM | NM_018136.5 | c.9730C>T | p.Arg3244Ter | stop_gained | 24/28 | ENST00000367409.9 | |
ASPM | NM_001206846.2 | c.4975C>T | p.Arg1659Ter | stop_gained | 23/27 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASPM | ENST00000367409.9 | c.9730C>T | p.Arg3244Ter | stop_gained | 24/28 | 1 | NM_018136.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151928Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250606Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135456
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1460880Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726746
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151928Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74186
ClinVar
Submissions by phenotype
Microcephaly 5, primary, autosomal recessive Pathogenic:3Other:1
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000021635, PMID:17849285). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
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 | - | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 09, 2022 | This variant is present in population databases (rs199422195, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg3244*) 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 premature translational stop signal has been observed in individual(s) with primary microcephaly (PMID: 17849285). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 21635). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 08, 2016 | The R3244X nonsense variant in the ASPM gene has been reported previously as a homozygous variant in multiple affected individuals in a family with MCPH (Gul et al., 2007). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at