8-125057574-C-G

Variant names:

• chr8-125057574-C-G
• rs80338866
• NM_014846.4:c.1857G>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_014846.4(WASHC5):​c.1857G>C​(p.Leu619Phe) variant causes a missense change involving the alteration of a non-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 Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L619V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WASHC5 NM_014846.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.53
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• Ritscher-Schinzel syndrome 1

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• hereditary spastic paraplegia 8

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Ritscher-Schinzel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_014846.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 8-125057574-C-G is Pathogenic according to our data. Variant chr8-125057574-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WASHC5	NM_014846.4	c.1857G>C	p.Leu619Phe	missense_variant	Exon 15 of 29	ENST00000318410.12	NP_055661.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WASHC5	ENST00000318410.12	c.1857G>C	p.Leu619Phe	missense_variant	Exon 15 of 29	1	NM_014846.4	ENSP00000318016.7
WASHC5	ENST00000517845.5	c.1413G>C	p.Leu471Phe	missense_variant	Exon 13 of 27	2		ENSP00000429676.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 8 Pathogenic:2

Jan 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 15, 2014

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ritscher-Schinzel syndrome;C1863704:Hereditary spastic paraplegia 8 Pathogenic:1

Mar 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 619 of the WASHC5 protein (p.Leu619Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 10797436, 17160902). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1162). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects WASHC5 function (PMID: 17160902). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	-0.059	T
PhyloP100		2.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.88
MutPred		0.84		Loss of helix (P = 0.1706);.;
MVP		0.93
MPC		0.92
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.83
gMVP		0.79
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs80338866; hg19: chr8-126069816;