rs142214506
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_018136.5(ASPM):c.3772G>A(p.Ala1258Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000552 in 1,612,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000032 ( 0 hom. )
Consequence
ASPM
NM_018136.5 missense
NM_018136.5 missense
Scores
10
9
Clinical Significance
Conservation
PhyloP100: 3.65
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.16328135).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ASPM | NM_018136.5 | c.3772G>A | p.Ala1258Thr | missense_variant | 16/28 | ENST00000367409.9 | NP_060606.3 | |
ASPM | NM_001206846.2 | c.3772G>A | p.Ala1258Thr | missense_variant | 16/27 | NP_001193775.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ASPM | ENST00000367409.9 | c.3772G>A | p.Ala1258Thr | missense_variant | 16/28 | 1 | NM_018136.5 | ENSP00000356379 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000277 AC: 42AN: 151896Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000681 AC: 17AN: 249734Hom.: 0 AF XY: 0.0000740 AC XY: 10AN XY: 135068
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GnomAD4 exome AF: 0.0000322 AC: 47AN: 1460172Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21AN XY: 726440
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GnomAD4 genome AF: 0.000277 AC: 42AN: 151896Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15AN XY: 74192
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 11, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 01, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 28, 2023 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ASPM protein function. ClinVar contains an entry for this variant (Variation ID: 388993). This variant has not been reported in the literature in individuals affected with ASPM-related conditions. This variant is present in population databases (rs142214506, gnomAD 0.09%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1258 of the ASPM protein (p.Ala1258Thr). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 22, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Uncertain
D;T;T
Sift4G
Uncertain
D;D;D
Polyphen
D;.;.
Vest4
MVP
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at