NM_014846.4:c.872G>A

Variant names:

• chr8-125075104-C-T
• rs753529606
• NM_014846.4:c.872G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_014846.4(WASHC5):​c.872G>A​(p.Ser291Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000014 in 1,432,158 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: WASHC5 NM_014846.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.11

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000014 (20/1432158) while in subpopulation EAS AF= 0.000507 (20/39468). AF 95% confidence interval is 0.000335. There are 0 homozygotes in gnomad4_exome. There are 9 alleles in male gnomad4_exome subpopulation. Median coverage is 26. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WASHC5	NM_014846.4	c.872G>A	p.Ser291Asn	missense_variant	Exon 8 of 29	ENST00000318410.12	NP_055661.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WASHC5	ENST00000318410.12	c.872G>A	p.Ser291Asn	missense_variant	Exon 8 of 29	1	NM_014846.4	ENSP00000318016.7
WASHC5	ENST00000517845.5	c.428G>A	p.Ser143Asn	missense_variant	Exon 6 of 27	2		ENSP00000429676.1
WASHC5	ENST00000523297.5	c.428G>A	p.Ser143Asn	missense_variant	Exon 7 of 7	3		ENSP00000427946.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 251044 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135696

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000140 AC: 20 AN: 1432158 Hom.: 0 Cov.: 26 AF XY: 0.0000126 AC XY: 9 AN XY: 714376

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000507

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 8;C4551776:Ritscher-Schinzel syndrome 1 Uncertain:1

Oct 12, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine with asparagine at codon 291 of the WASHC5 protein (p.Ser291Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs753529606, ExAC 0.01%). This variant has not been reported in the literature in individuals with WASHC5-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;.;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Uncertain	-0.095	T
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.5	N;N;N
REVEL	Uncertain	0.46
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.27	T;T;.
Polyphen		0.61	P;.;.
Vest4		0.84
MutPred		0.77		Loss of sheet (P = 0.0357);.;.;
MVP		0.83
MPC		0.23
ClinPred		0.28	T
GERP RS		4.8
Varity_R		0.32
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs753529606; hg19: chr8-126087346;