rs1554593899
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_014846.4(WASHC5):c.1772C>T(p.Ser591Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S591P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_014846.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WASHC5 | NM_014846.4 | c.1772C>T | p.Ser591Phe | missense_variant | 15/29 | ENST00000318410.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WASHC5 | ENST00000318410.12 | c.1772C>T | p.Ser591Phe | missense_variant | 15/29 | 1 | NM_014846.4 | P1 | |
WASHC5 | ENST00000517845.5 | c.1328C>T | p.Ser443Phe | missense_variant | 13/27 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 29
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 8 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Aug 07, 2017 | - - |
Ritscher-Schinzel syndrome;C1863704:Hereditary spastic paraplegia 8 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 20, 2022 | 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 expected to disrupt WASHC5 protein function. ClinVar contains an entry for this variant (Variation ID: 495056). This missense change has been observed in individuals with clinical features of hereditary spastic paraplegia (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 591 of the WASHC5 protein (p.Ser591Phe). This variant disrupts the p.Ser591 amino acid residue in WASHC5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24824269). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at