rs1556301016
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_001353921.2(ARHGEF9):c.1480G>A(p.Ala494Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,094,222 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A494A) has been classified as Likely benign.
Frequency
Consequence
NM_001353921.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARHGEF9 | NM_001353921.2 | c.1480G>A | p.Ala494Thr | missense_variant | 10/10 | ENST00000671741.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARHGEF9 | ENST00000671741.2 | c.1480G>A | p.Ala494Thr | missense_variant | 10/10 | NM_001353921.2 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 exomes AF: 0.00000574 AC: 1AN: 174340Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 59616
GnomAD4 exome AF: 0.0000101 AC: 11AN: 1094222Hom.: 0 Cov.: 31 AF XY: 0.0000139 AC XY: 5AN XY: 359856
GnomAD4 genome ? Cov.: 22
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 19, 2020 | The c.1459G>A (p.A487T) alteration is located in coding exon 10 of the ARHGEF9 gene. This alteration results from a G to A substitution at nucleotide position 1459, causing the alanine (A) at amino acid position 487 to be replaced by a threonine (T). Based on data from the Genome Aggregation Database (gnomAD) database, the ARHGEF9 c.1459G>A alteration was observed in <0.01% (1/174340) of total alleles studied. This amino acid position is not well conserved in available vertebrate species. The p.A487T alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Developmental and epileptic encephalopathy, 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 04, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 487 of the ARHGEF9 protein (p.Ala487Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ARHGEF9-related conditions. ClinVar contains an entry for this variant (Variation ID: 533663). 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 ARHGEF9 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at