rs112997359
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_018136.5(ASPM):āc.1949C>Gā(p.Ser650Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000659 in 1,609,238 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_018136.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASPM | NM_018136.5 | c.1949C>G | p.Ser650Cys | missense_variant | 4/28 | ENST00000367409.9 | |
ASPM | NM_001206846.2 | c.1949C>G | p.Ser650Cys | missense_variant | 4/27 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASPM | ENST00000367409.9 | c.1949C>G | p.Ser650Cys | missense_variant | 4/28 | 1 | NM_018136.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000171 AC: 26AN: 152160Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251410Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135880
GnomAD4 exome AF: 0.0000487 AC: 71AN: 1456960Hom.: 1 Cov.: 30 AF XY: 0.0000510 AC XY: 37AN XY: 725138
GnomAD4 genome ? AF: 0.000230 AC: 35AN: 152278Hom.: 1 Cov.: 33 AF XY: 0.000282 AC XY: 21AN XY: 74464
ClinVar
Submissions by phenotype
Microcephaly 5, primary, autosomal recessive Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 27, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 29, 2020 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 28, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 650 of the ASPM protein (p.Ser650Cys). This variant is present in population databases (rs112997359, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with ASPM-related conditions. ClinVar contains an entry for this variant (Variation ID: 157789). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ASPM protein function. 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 14, 2021 | The c.1949C>G (p.S650C) alteration is located in exon 4 (coding exon 4) of the ASPM gene. This alteration results from a C to G substitution at nucleotide position 1949, causing the serine (S) at amino acid position 650 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at