chr8-125032351-T-C
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_014846.4(WASHC5):āc.3225A>Gā(p.Pro1075=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00231 in 1,614,158 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.013 ( 35 hom., cov: 30)
Exomes š: 0.0012 ( 28 hom. )
Consequence
WASHC5
NM_014846.4 synonymous
NM_014846.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -8.54
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 Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
Variant 8-125032351-T-C is Benign according to our data. Variant chr8-125032351-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 361712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-8.53 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0128 (1950/152298) while in subpopulation AFR AF= 0.0451 (1876/41562). AF 95% confidence interval is 0.0434. There are 35 homozygotes in gnomad4. There are 932 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 35 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WASHC5 | NM_014846.4 | c.3225A>G | p.Pro1075= | synonymous_variant | 27/29 | ENST00000318410.12 | |
WASHC5 | NM_001330609.2 | c.2781A>G | p.Pro927= | synonymous_variant | 26/28 | ||
WASHC5 | XM_047422502.1 | c.3225A>G | p.Pro1075= | synonymous_variant | 28/30 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WASHC5 | ENST00000318410.12 | c.3225A>G | p.Pro1075= | synonymous_variant | 27/29 | 1 | NM_014846.4 | P1 | |
WASHC5 | ENST00000517845.5 | c.2781A>G | p.Pro927= | synonymous_variant | 25/27 | 2 | |||
WASHC5 | ENST00000519042.2 | n.364A>G | non_coding_transcript_exon_variant | 1/3 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0128 AC: 1948AN: 152180Hom.: 35 Cov.: 30
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GnomAD3 exomes AF: 0.00329 AC: 826AN: 251140Hom.: 21 AF XY: 0.00234 AC XY: 317AN XY: 135700
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GnomAD4 exome AF: 0.00122 AC: 1784AN: 1461860Hom.: 28 Cov.: 31 AF XY: 0.00100 AC XY: 729AN XY: 727230
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GnomAD4 genome AF: 0.0128 AC: 1950AN: 152298Hom.: 35 Cov.: 30 AF XY: 0.0125 AC XY: 932AN XY: 74472
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 03, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Hereditary spastic paraplegia 8 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Hereditary spastic paraplegia 8;C4551776:Ritscher-Schinzel syndrome 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 27, 2021 | - - |
Hereditary spastic paraplegia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jan 17, 2022 | - - |
Ritscher-Schinzel syndrome;C1863704:Hereditary spastic paraplegia 8 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
WASHC5-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 07, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 13, 2018 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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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