8-125043821-A-G
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_014846.4(WASHC5):c.2850+4T>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,597,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
WASHC5
NM_014846.4 splice_donor_region, intron
NM_014846.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0004650
2
Clinical Significance
Conservation
PhyloP100: 0.0430
Genes affected
WASHC5 (HGNC:28984): (WASH complex subunit 5) This gene encodes a 134 kDa protein named strumpellin that is predicted to have multiple transmembrane domains and a spectrin-repeat-containing domain. This ubiquitously expressed gene has its highest expression in skeletal muscle. The protein is named for Strumpell disease; a form of hereditary spastic paraplegia (HSP). Spastic paraplegias are a diverse group of disorders in which the autosomal dominant forms are characterized by progressive, lower extremity spasticity caused by axonal degeneration in the terminal portions of the longest descending and ascending corticospinal tracts. More than 30 loci (SPG1-33) have been implicated in hereditary spastic paraplegia diseases. [provided by RefSeq, Aug 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.47).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
WASHC5 | NM_014846.4 | c.2850+4T>C | splice_donor_region_variant, intron_variant | ENST00000318410.12 | NP_055661.3 | |||
WASHC5-AS1 | NR_170219.1 | n.97-678A>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
WASHC5 | ENST00000318410.12 | c.2850+4T>C | splice_donor_region_variant, intron_variant | 1 | NM_014846.4 | ENSP00000318016 | P1 | |||
WASHC5-AS1 | ENST00000519140.1 | n.97-678A>G | intron_variant, non_coding_transcript_variant | 4 | ||||||
WASHC5 | ENST00000517845.5 | c.2406+4T>C | splice_donor_region_variant, intron_variant | 2 | ENSP00000429676 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152230Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000319 AC: 8AN: 251072Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135700
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GnomAD4 exome AF: 0.000113 AC: 164AN: 1445424Hom.: 0 Cov.: 28 AF XY: 0.000111 AC XY: 80AN XY: 720266
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GnomAD4 genome AF: 0.0000591 AC: 9AN: 152230Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74374
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Ritscher-Schinzel syndrome;C1863704:Hereditary spastic paraplegia 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 30, 2022 | 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 361715). This variant has not been reported in the literature in individuals affected with WASHC5-related conditions. This variant is present in population databases (rs770743674, gnomAD 0.007%). This sequence change falls in intron 23 of the WASHC5 gene. It does not directly change the encoded amino acid sequence of the WASHC5 protein. It affects a nucleotide within the consensus splice site. - |
WASHC5-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 08, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at