rs11542889

Positions:

• chr8-125032285-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The ENST00000318410.12(WASHC5):​c.3291G>A​(p.Ala1097=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0535 in 1,613,874 control chromosomes in the GnomAD database, including 6,907 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (3087 hom., cov: 30)
  • Exomes 𝑓: 0.045 (3820 hom.)
• Consequence: WASHC5 ENST00000318410.12 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.71

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 8-125032285-C-T is Benign according to our data. Variant chr8-125032285-C-T is described in ClinVar as [Benign]. Clinvar id is 129376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-125032285-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.71 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WASHC5	NM_014846.4	c.3291G>A	p.Ala1097=	synonymous_variant	27/29	ENST00000318410.12	NP_055661.3
WASHC5	NM_001330609.2	c.2847G>A	p.Ala949=	synonymous_variant	26/28		NP_001317538.1
WASHC5	XM_047422502.1	c.3291G>A	p.Ala1097=	synonymous_variant	28/30		XP_047278458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WASHC5	ENST00000318410.12	c.3291G>A	p.Ala1097=	synonymous_variant	27/29	1	NM_014846.4	ENSP00000318016	P1
WASHC5	ENST00000517845.5	c.2847G>A	p.Ala949=	synonymous_variant	25/27	2		ENSP00000429676
WASHC5	ENST00000519042.2	n.430G>A		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20438 AN: 151968 Hom.: 3064 Cov.: 30

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0669

Gnomad ASJ AF: 0.0309

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0191

Gnomad FIN AF: 0.0918

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0380

Gnomad OTH AF: 0.111

GnomAD3 exomes AF: 0.0609 AC: 15303 AN: 251232 Hom.: 1447 AF XY: 0.0546 AC XY: 7412 AN XY: 135764

Gnomad AFR exome AF: 0.382

Gnomad AMR exome AF: 0.0401

Gnomad ASJ exome AF: 0.0339

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0205

Gnomad FIN exome AF: 0.0842

Gnomad NFE exome AF: 0.0403

Gnomad OTH exome AF: 0.0556

GnomAD4 exome AF: 0.0451 AC: 65864 AN: 1461788 Hom.: 3820 Cov.: 32 AF XY: 0.0439 AC XY: 31909 AN XY: 727216

Gnomad4 AFR exome AF: 0.387

Gnomad4 AMR exome AF: 0.0439

Gnomad4 ASJ exome AF: 0.0332

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0207

Gnomad4 FIN exome AF: 0.0784

Gnomad4 NFE exome AF: 0.0361

Gnomad4 OTH exome AF: 0.0583

GnomAD4 genome AF: 0.135 AC: 20509 AN: 152086 Hom.: 3087 Cov.: 30 AF XY: 0.134 AC XY: 9932 AN XY: 74358

Gnomad4 AFR AF: 0.373

Gnomad4 AMR AF: 0.0669

Gnomad4 ASJ AF: 0.0309

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.0183

Gnomad4 FIN AF: 0.0918

Gnomad4 NFE AF: 0.0380

Gnomad4 OTH AF: 0.109

Alfa AF: 0.0639 Hom.: 1001

Bravo AF: 0.143

Asia WGS AF: 0.0420 AC: 146 AN: 3478

EpiCase AF: 0.0394

EpiControl AF: 0.0452

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary spastic paraplegia 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 27, 2017	- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	0.17
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs11542889; hg19: chr8-126044527;