rs770593694
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_020631.6(PLEKHG5):c.2542C>T(p.Arg848Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000708 in 1,609,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000074 ( 0 hom. )
Consequence
PLEKHG5
NM_020631.6 stop_gained
NM_020631.6 stop_gained
Scores
2
2
3
Clinical Significance
Conservation
PhyloP100: 0.683
Genes affected
PLEKHG5 (HGNC:29105): (pleckstrin homology and RhoGEF domain containing G5) This gene encodes a protein that activates the nuclear factor kappa B (NFKB1) signaling pathway. Mutations in this gene are associated with autosomal recessive distal spinal muscular atrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.159 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-6468294-G-A is Pathogenic according to our data. Variant chr1-6468294-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 566096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLEKHG5 | NM_020631.6 | c.2542C>T | p.Arg848Ter | stop_gained | 20/21 | ENST00000377728.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLEKHG5 | ENST00000377728.8 | c.2542C>T | p.Arg848Ter | stop_gained | 20/21 | 2 | NM_020631.6 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152204Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000168 AC: 4AN: 238516Hom.: 0 AF XY: 0.0000154 AC XY: 2AN XY: 130112
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GnomAD4 exome AF: 0.0000741 AC: 108AN: 1457654Hom.: 0 Cov.: 32 AF XY: 0.0000648 AC XY: 47AN XY: 724766
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neuronopathy, distal hereditary motor, autosomal recessive 4;C3809309:Charcot-Marie-Tooth disease recessive intermediate C Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change creates a premature translational stop signal (p.Arg848*) in the PLEKHG5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PLEKHG5 are known to be pathogenic (PMID: 17564964, 23777631). This variant is present in population databases (rs770593694, gnomAD 0.005%). 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: 566096). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 26, 2021 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Database of Genomic Variants; McDonald et al., 2014); Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;A;A;A;A;A;A;A;A;A;A;A;D
Vest4
GERP RS
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at