rs193251130
Positions:
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_018136.5(ASPM):āc.9539A>Cā(p.Gln3180Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,613,386 control chromosomes in the GnomAD database, including 113 homozygotes. 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: š 0.0013 ( 8 hom., cov: 32)
Exomes š: 0.0023 ( 105 hom. )
Consequence
ASPM
NM_018136.5 missense
NM_018136.5 missense
Scores
5
13
Clinical Significance
Conservation
PhyloP100: 0.150
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 Benign. Variant got -13 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.032000035).
BP6
Variant 1-197090947-T-G is Benign according to our data. Variant chr1-197090947-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 21628.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, not_provided=1, Benign=6, Uncertain_significance=1}. Variant chr1-197090947-T-G is described in Lovd as [Likely_benign]. Variant chr1-197090947-T-G is described in Lovd as [Pathogenic].
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00129 (196/152240) while in subpopulation SAS AF= 0.0377 (182/4822). AF 95% confidence interval is 0.0333. There are 8 homozygotes in gnomad4. There are 140 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 8 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ASPM | NM_018136.5 | c.9539A>C | p.Gln3180Pro | missense_variant | 23/28 | ENST00000367409.9 | NP_060606.3 | |
ASPM | NM_001206846.2 | c.4784A>C | p.Gln1595Pro | missense_variant | 22/27 | NP_001193775.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ASPM | ENST00000367409.9 | c.9539A>C | p.Gln3180Pro | missense_variant | 23/28 | 1 | NM_018136.5 | ENSP00000356379 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00131 AC: 199AN: 152122Hom.: 8 Cov.: 32
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GnomAD3 exomes AF: 0.00467 AC: 1171AN: 250508Hom.: 35 AF XY: 0.00616 AC XY: 834AN XY: 135344
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GnomAD4 exome AF: 0.00228 AC: 3334AN: 1461146Hom.: 105 Cov.: 32 AF XY: 0.00326 AC XY: 2372AN XY: 726868
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GnomAD4 genome AF: 0.00129 AC: 196AN: 152240Hom.: 8 Cov.: 32 AF XY: 0.00188 AC XY: 140AN XY: 74428
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:9Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:5
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 14, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 28, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | ASPM: BP4, BS1, BS2 - |
Microcephaly 5, primary, autosomal recessive Uncertain:1Benign:2Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Benign, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | - | The homozygous p.Gln3180Pro variant in ASPM has been identified in 4 siblings from 1 family with primary microcephaly (PMID: 16673149), and has been identified in >3% of South Asian chromosomes and 19 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive primary microcephaly. - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 07, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 22, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.
MutationTaster
Benign
A;A;A
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D
REVEL
Benign
Sift
Benign
T;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;.;.
Vest4
MVP
ClinPred
T
GERP RS
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