chr8-125047289-T-C

Position:

• chr8-125047289-T-C

Variant summary

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

The NM_014846.4(WASHC5):​c.2422A>G​(p.Ile808Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00034 in 1,613,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: WASHC5 NM_014846.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 8.01

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 amr. gnomad4 allele frequency = 0.000217 (33/152142) while in subpopulation AMR AF= 0.000524 (8/15270). AF 95% confidence interval is 0.000261. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 32. 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/exons	MANE	Protein	UniProt
WASHC5	NM_014846.4	c.2422A>G	p.Ile808Val	missense_variant	20/29	ENST00000318410.12	NP_055661.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WASHC5	ENST00000318410.12	c.2422A>G	p.Ile808Val	missense_variant	20/29	1	NM_014846.4	ENSP00000318016.7
WASHC5	ENST00000517845.5	c.1978A>G	p.Ile660Val	missense_variant	18/27	2		ENSP00000429676.1
WASHC5	ENST00000530856.1	n.69A>G		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000139 AC: 35 AN: 251334 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135836

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000353 AC: 516 AN: 1461730 Hom.: 0 Cov.: 31 AF XY: 0.000338 AC XY: 246 AN XY: 727182

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000435

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74314

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000299 Hom.: 0

Bravo AF: 0.000374

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 10, 2024	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with clinical features associated with this gene. Computational tools disagree on the variant's effect on normal protein function. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 21, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 23, 2020	- -

Hereditary spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 22, 2016

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 07, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 808 of the WASHC5 protein (p.Ile808Val). This variant is present in population databases (rs144507279, gnomAD 0.03%). This missense change has been observed in individual(s) with hereditary spastic paraplegia (HSP) (PMID: 27957547). ClinVar contains an entry for this variant (Variation ID: 374553). 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 not expected to disrupt WASHC5 protein function with a negative predictive value of 80%. 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	Benign	0.15
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Uncertain	0.70	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.72	N;N
REVEL	Uncertain	0.60
Sift	Benign	0.15	T;T
Sift4G	Benign	0.086	T;T
Polyphen		0.70	P;B
Vest4		0.78
MVP		0.88
MPC		0.34
ClinPred		0.063	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.54

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: rs144507279; hg19: chr8-126059531;