rs199422142
Variant summary
Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2
The NM_018136.5(ASPM):c.1406_1413delATCCTAAA(p.Asn469IlefsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,196 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as not provided (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
ASPM
NM_018136.5 frameshift
NM_018136.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.52
Publications
3 publications found
Genes affected
ASPM (HGNC:19048): (assembly factor for spindle microtubules) This gene is the human ortholog of the Drosophila melanogaster 'abnormal spindle' gene (asp), which is essential for normal mitotic spindle function in embryonic neuroblasts. Studies in mouse also suggest a role of this gene in mitotic spindle regulation, with a preferential role in regulating neurogenesis. Mutations in this gene are associated with microcephaly primary type 5. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2011]
ASPM Gene-Disease associations (from GenCC):
- microcephaly 5, primary, autosomal recessiveInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
- autosomal recessive primary microcephalyInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 10 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ASPM | NM_018136.5 | c.1406_1413delATCCTAAA | p.Asn469IlefsTer9 | frameshift_variant | Exon 3 of 28 | ENST00000367409.9 | NP_060606.3 | |
| ASPM | NM_001206846.2 | c.1406_1413delATCCTAAA | p.Asn469IlefsTer9 | frameshift_variant | Exon 3 of 27 | NP_001193775.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461196Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 726938 show subpopulations
GnomAD4 exome
AF:
AC:
3
AN:
1461196
Hom.:
AF XY:
AC XY:
2
AN XY:
726938
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33450
American (AMR)
AF:
AC:
0
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26124
East Asian (EAS)
AF:
AC:
0
AN:
39664
South Asian (SAS)
AF:
AC:
0
AN:
86224
European-Finnish (FIN)
AF:
AC:
0
AN:
53414
Middle Eastern (MID)
AF:
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
AC:
3
AN:
1111486
Other (OTH)
AF:
AC:
0
AN:
60354
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.408
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: not provided
Submissions summary: Other:1
Revision: no classification provided
LINK: link
Submissions by phenotype
Microcephaly 5, primary, autosomal recessive Other:1
-
GeneReviews
Significance:not provided
Review Status:no classification provided
Collection Method:literature only
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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