rs776034810
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_018136.5(ASPM):c.4720C>T(p.Gln1574Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,630 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 Likely 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 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASPM | NM_018136.5 | c.4720C>T | p.Gln1574Ter | stop_gained | 18/28 | ENST00000367409.9 | |
ASPM | NM_001206846.2 | c.4066-8367C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASPM | ENST00000367409.9 | c.4720C>T | p.Gln1574Ter | stop_gained | 18/28 | 1 | NM_018136.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249480Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134904
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460630Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1AN XY: 726610
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Autosomal recessive primary microcephaly Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 22, 2016 | The p.Gln1574X (NM_018136.4 c.4720C>T) variant in ASPM has not been reported in the literature. This nonsense variant leads to a premature termination codon at position 1574, which is predicted to lead to a truncated or absent protein. Bial lelic loss of function of the ASPM gene has been associated with primary microce phaly type 5. This variant has been identified in 1/6550 of Finnish chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs776034810). Although this variant has been seen in the general population, it s frequency is low enough to be consistent with a recessive carrier frequency. In summary, although additional studies are required to fully establish a null e ffect on the protein, the p.Gln1574X variant in ASPM is likely pathogenic for pr imary microcephaly type 5 in an autosomal recessive manner based upon its predic ted functional impact. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at