chrX-63638129-C-T
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_001353921.2(ARHGEF9):c.1471G>A(p.Asp491Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000216 in 1,204,435 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts 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. D491E) has been classified as Benign.
Frequency
Consequence
NM_001353921.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARHGEF9 | NM_001353921.2 | c.1471G>A | p.Asp491Asn | missense_variant | 10/10 | ENST00000671741.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARHGEF9 | ENST00000671741.2 | c.1471G>A | p.Asp491Asn | missense_variant | 10/10 | NM_001353921.2 | A1 |
Frequencies
GnomAD3 genomes AF: 0.000126 AC: 14AN: 110725Hom.: 0 Cov.: 22 AF XY: 0.0000910 AC XY: 3AN XY: 32955
GnomAD3 exomes AF: 0.0000175 AC: 3AN: 171655Hom.: 0 AF XY: 0.0000349 AC XY: 2AN XY: 57339
GnomAD4 exome AF: 0.0000110 AC: 12AN: 1093710Hom.: 0 Cov.: 31 AF XY: 0.0000111 AC XY: 4AN XY: 359462
GnomAD4 genome AF: 0.000126 AC: 14AN: 110725Hom.: 0 Cov.: 22 AF XY: 0.0000910 AC XY: 3AN XY: 32955
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 24, 2022 | The c.1450G>A (p.D484N) alteration is located in coding exon 10 of the ARHGEF9 gene. This alteration results from a G to A substitution at nucleotide position 1450, causing the aspartic acid (D) at amino acid position 484 to be replaced by an asparagine (N). This alteration is rare in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the ARHGEF9 c.1450G>A alteration was observed in 4 among 188,266 total alleles studied (0.002%), having been observed in 3 total hemizygotes and 3/84,024 (0.004%) European (Non-Finnish) alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), this alteration was not observed among 6,503 total alleles studied. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project. Rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012; please note that some variants may appear to be rare due to ethnic underrepresentation in the database). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.D484 amino acid is conserved through available reptile species. The alteration is predicted benign by in silico models:_x000D_ _x000D_ The p.D484N alteration is predicted to be benign by Polyphen and tolerated by SIFT in silico analyses. 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 | Dec 19, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 484 of the ARHGEF9 protein (p.Asp484Asn). 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 missense change has been observed in individual(s) with developmental and epileptic encephalopathy (PMID: 32593896). ClinVar contains an entry for this variant (Variation ID: 383721). 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 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. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 27, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at