rs878854987

Positions:

• chr8-125050626-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014846.4(WASHC5):​c.2137G>A​(p.Glu713Lys) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WASHC5 NM_014846.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.84

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WASHC5	NM_014846.4	c.2137G>A	p.Glu713Lys	missense_variant	18/29	ENST00000318410.12	NP_055661.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WASHC5	ENST00000318410.12	c.2137G>A	p.Glu713Lys	missense_variant	18/29	1	NM_014846.4	ENSP00000318016	P1
WASHC5	ENST00000517845.5	c.1693G>A	p.Glu565Lys	missense_variant	16/27	2		ENSP00000429676

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 10, 2015

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This sequence change has not been published in the literature and is not present in population databases. This sequence change replaces glutamic acid with lysine at codon 713 of the KIAA0196 protein (p.Glu713Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.65	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.3	D;D
REVEL	Pathogenic	0.82
Sift	Benign	0.057	T;T
Sift4G	Benign	0.062	T;T
Polyphen		0.46	P;D
Vest4		0.97
MutPred		0.70		Gain of MoRF binding (P = 0.0026);.;
MVP		0.93
MPC		0.94
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.52
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs878854987; hg19: chr8-126062868;