rs80338867

Positions:

chr8-125056817-C-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The ENST00000318410.12(WASHC5):c.1876G>T(p.Val626Phe) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

WASHC5
ENST00000318410.12 missense, splice_region

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 7.84

Variant links:

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]

WASHC5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in ENST00000318410.12

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.924

PP5

Variant 8-125056817-C-A is Pathogenic according to our data. Variant chr8-125056817-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WASHC5	NM_014846.4 linkuse as main transcript	c.1876G>T	p.Val626Phe	missense_variant, splice_region_variant	16/29	ENST00000318410.12	NP_055661.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WASHC5	ENST00000318410.12 linkuse as main transcript	c.1876G>T	p.Val626Phe	missense_variant, splice_region_variant	16/29	1	NM_014846.4	ENSP00000318016	P1
WASHC5	ENST00000517845.5 linkuse as main transcript	c.1432G>T	p.Val478Phe	missense_variant, splice_region_variant	14/27	2		ENSP00000429676

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 8

Pathogenic:3Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2007	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000001161). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	WASHC5: PP1:Strong, PM2, PS4:Moderate, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2023	Published functional studies demonstrate discrepant effects of this variant on endosomal tubulation (Freeman et al., 2013; Lee et al., 2020) and protein interactions (Valdmanis et al., 2007; Huttlin et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34184482, 25525159, 30072228, 24451228, 23881105, 35667337, 26659599, 26147798, 28569743, 28514442, 31911435, 26973516, 17160902, 28181327, 20301727, 34312900, 30061306, 23085491) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 07, 2022	This variant segregates with spastic paraplegia in multiple families. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. See PMID: 17160902, 31911435. -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2023

The c.1876G>T (p.V626F) alteration is located in exon 16 (coding exon 15) of the WASHC5 gene. This alteration results from a G to T substitution at nucleotide position 1876, causing the valine (V) at amino acid position 626 to be replaced by a phenylalanine (F). This variant impacts the first base pair of coding exon 15. This variant is expected to be causative of WASHC5-related spastic paraplegia; however, its clinical significance for Ritscher-Schinzel syndrome is unclear. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been previously reported in the heterozygous state in multiple individuals with hereditary spastic paraplegia (Valdmanis, 2007). This amino acid position is highly conserved in available vertebrate species. Functional evidence suggests that p.V626F impacts protein function and CAV1-dependent, integrin-mediated cell adhesion; however, the physiological relevance of these findings is unclear (Valdmanis, 2007; Freeman, 2013; Lee, 2020). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Hereditary spastic paraplegia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 13, 2021

- -

Ritscher-Schinzel syndrome;C1863704:Hereditary spastic paraplegia 8

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 19, 2020

For these reasons, this variant has been classified as Pathogenic. Experimental studies with zebrafish knockdowns showed that a WASHC5 protein with this variant failed to rescue disease phenotype, suggesting that this variant functionally impairs the WASHC5 protein (PMID: 17160902). This variant has been reported to segregate with disease in three families affected with hereditary spastic paraplegia (PMID: 17160902). This gene is also known as KIAA0196 and/or strumpellin in the literature. ClinVar contains an entry for this variant (Variation ID: 1161). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with phenylalanine at codon 626 of the WASHC5 protein (p.Val626Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;.

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Pathogenic

1.0

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.9

D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.94

MutPred

0.69

Gain of ubiquitination at K625 (P = 0.0817);.;

MVP

0.94

MPC

1.0

ClinPred

0.99

GERP RS

5.6

Varity_R

0.83

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.16

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over