8-125057660-A-G

Position:

• chr8-125057660-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_014846.4(WASHC5):​c.1771T>C​(p.Ser591Pro) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WASHC5 NM_014846.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 8-125057660-A-G is Pathogenic according to our data. Variant chr8-125057660-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 463137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-125057660-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WASHC5	NM_014846.4	c.1771T>C	p.Ser591Pro	missense_variant	15/29	ENST00000318410.12	NP_055661.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WASHC5	ENST00000318410.12	c.1771T>C	p.Ser591Pro	missense_variant	15/29	1	NM_014846.4	ENSP00000318016	P1
WASHC5	ENST00000517845.5	c.1327T>C	p.Ser443Pro	missense_variant	13/27	2		ENSP00000429676

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 8 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	May 09, 2018	- -

Ritscher-Schinzel syndrome 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Genomics England Pilot Project, Genomics England

-

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 03, 2021

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with hereditary spastic paraplegia (PMID: 24824269, Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 463137). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with proline at codon 591 of the WASHC5 protein (p.Ser591Pro). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.93	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.98	D;D
Vest4		0.91
MutPred		0.82		Gain of relative solvent accessibility (P = 0.0082);.;
MVP		0.96
MPC		0.99
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.91
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs1554593901; hg19: chr8-126069902;