rs144750655
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PVS1_ModeratePM2PP5BS1_Supporting
The NM_020631.6(PLEKHG5):c.440-2A>G variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00047 in 1,613,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_020631.6 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PLEKHG5 | NM_020631.6 | c.440-2A>G | splice_acceptor_variant | ENST00000377728.8 | NP_065682.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PLEKHG5 | ENST00000377728.8 | c.440-2A>G | splice_acceptor_variant | 2 | NM_020631.6 | ENSP00000366957 | P2 |
Frequencies
GnomAD3 genomes AF: 0.000256 AC: 39AN: 152186Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000165 AC: 41AN: 249072Hom.: 0 AF XY: 0.000163 AC XY: 22AN XY: 135260
GnomAD4 exome AF: 0.000492 AC: 719AN: 1461024Hom.: 0 Cov.: 38 AF XY: 0.000464 AC XY: 337AN XY: 726802
GnomAD4 genome AF: 0.000256 AC: 39AN: 152304Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17AN XY: 74462
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 05, 2019 | PVS1, PM2 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 14, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 24, 2022 | Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31589614) - |
Neuronopathy, distal hereditary motor, autosomal recessive 4;C3809309:Charcot-Marie-Tooth disease recessive intermediate C Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 04, 2024 | This sequence change affects an acceptor splice site in intron 6 of the PLEKHG5 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PLEKHG5 are known to be pathogenic (PMID: 17564964, 23777631). This variant is present in population databases (rs144750655, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PLEKHG5-related conditions. ClinVar contains an entry for this variant (Variation ID: 423836). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 03, 2022 | The c.440-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 6 in the PLEKHG5 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown. This nucleotide position is poorly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at