rs199422146
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_018136.5(ASPM):c.1729_1730delAG(p.Ser577fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,796 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S577S) has been classified as Likely benign. 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/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ASPM | NM_018136.5 | c.1729_1730delAG | p.Ser577fs | frameshift_variant | 3/28 | ENST00000367409.9 | NP_060606.3 | |
ASPM | NM_001206846.2 | c.1729_1730delAG | p.Ser577fs | frameshift_variant | 3/27 | NP_001193775.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ASPM | ENST00000367409.9 | c.1729_1730delAG | p.Ser577fs | frameshift_variant | 3/28 | 1 | NM_018136.5 | ENSP00000356379.4 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152080Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251256Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135830
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461716Hom.: 0 AF XY: 0.0000124 AC XY: 9AN XY: 727164
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152080Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74316
ClinVar
Submissions by phenotype
Microcephaly 5, primary, autosomal recessive Pathogenic:2Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 27, 2020 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 14574646, 31589614) - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 24, 2022 | ClinVar contains an entry for this variant (Variation ID: 402179). This variant is also known as c.1727delAG. This premature translational stop signal has been observed in individual(s) with primary microcephaly (PMID: 14574646). This variant is present in population databases (rs747238090, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Ser577Argfs*33) 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). For these reasons, this variant has been classified as Pathogenic. - |
Microcephaly Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at