chr1-197100510-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_018136.5(ASPM):āc.8741T>Cā(p.Ile2914Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00027 in 1,610,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2914L) has been classified as Uncertain significance.
Frequency
Consequence
NM_018136.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASPM | NM_018136.5 | c.8741T>C | p.Ile2914Thr | missense_variant | 18/28 | ENST00000367409.9 | |
ASPM | NM_001206846.2 | c.4066-4346T>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASPM | ENST00000367409.9 | c.8741T>C | p.Ile2914Thr | missense_variant | 18/28 | 1 | NM_018136.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000191 AC: 29AN: 151736Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000176 AC: 44AN: 249310Hom.: 0 AF XY: 0.000141 AC XY: 19AN XY: 134870
GnomAD4 exome AF: 0.000278 AC: 406AN: 1458732Hom.: 0 Cov.: 30 AF XY: 0.000267 AC XY: 194AN XY: 725614
GnomAD4 genome AF: 0.000191 AC: 29AN: 151736Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74076
ClinVar
Submissions by phenotype
Microcephaly 5, primary, autosomal recessive Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 25, 2021 | The c.8741T>C (p.I2914T) alteration is located in exon 18 (coding exon 18) of the ASPM gene. This alteration results from a T to C substitution at nucleotide position 8741, causing the isoleucine (I) at amino acid position 2914 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 18, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2914 of the ASPM protein (p.Ile2914Thr). This variant is present in population databases (rs200856894, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of Seckel syndrome (PMID: 23611254). ClinVar contains an entry for this variant (Variation ID: 157899). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 18, 2018 | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at