rs765798033
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_018136.5(ASPM):c.2761G>T(p.Ala921Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000249 in 1,605,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/26 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_018136.5 missense, splice_region
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.2761G>T | p.Ala921Ser | missense_variant, splice_region_variant | 10/28 | ENST00000367409.9 | |
ASPM | NM_001206846.2 | c.2761G>T | p.Ala921Ser | missense_variant, splice_region_variant | 10/27 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASPM | ENST00000367409.9 | c.2761G>T | p.Ala921Ser | missense_variant, splice_region_variant | 10/28 | 1 | NM_018136.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000198 AC: 3AN: 151788Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000409 AC: 1AN: 244224Hom.: 0 AF XY: 0.00000755 AC XY: 1AN XY: 132514
GnomAD4 exome AF: 0.0000254 AC: 37AN: 1453990Hom.: 0 Cov.: 31 AF XY: 0.0000318 AC XY: 23AN XY: 723526
GnomAD4 genome AF: 0.0000198 AC: 3AN: 151788Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74100
ClinVar
Submissions by phenotype
Microcephaly 5, primary, autosomal recessive Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 24, 2021 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 234802). This variant has not been reported in the literature in individuals affected with ASPM-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with serine at codon 921 of the ASPM protein (p.Ala921Ser). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and serine. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 25, 2019 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at