rs7812319

Positions:

• chr8-125078852-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014846.4(WASHC5):​c.597A>G​(p.Pro199Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0312 in 1,613,884 control chromosomes in the GnomAD database, including 1,741 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (128 hom., cov: 31)
  • Exomes 𝑓: 0.031 (1613 hom.)
• Consequence: WASHC5 NM_014846.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.638

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 8-125078852-T-C is Benign according to our data. Variant chr8-125078852-T-C is described in ClinVar as [Benign]. Clinvar id is 129377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-125078852-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.638 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WASHC5	NM_014846.4	c.597A>G	p.Pro199Pro	synonymous_variant	6/29	ENST00000318410.12	NP_055661.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WASHC5	ENST00000318410.12	c.597A>G	p.Pro199Pro	synonymous_variant	6/29	1	NM_014846.4	ENSP00000318016.7
WASHC5	ENST00000517845.5	c.153A>G	p.Pro51Pro	synonymous_variant	4/27	2		ENSP00000429676.1
WASHC5	ENST00000523297.5	c.153A>G	p.Pro51Pro	synonymous_variant	5/7	3		ENSP00000427946.1

Frequencies

GnomAD3 genomes AF: 0.0285 AC: 4341 AN: 152070 Hom.: 128 Cov.: 31

Gnomad AFR AF: 0.0283

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.0699

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.0197

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0217

Gnomad OTH AF: 0.0349

GnomAD3 exomes AF: 0.0425 AC: 10682 AN: 251400 Hom.: 552 AF XY: 0.0470 AC XY: 6390 AN XY: 135866

Gnomad AFR exome AF: 0.0276

Gnomad AMR exome AF: 0.0131

Gnomad ASJ exome AF: 0.0164

Gnomad EAS exome AF: 0.0758

Gnomad SAS exome AF: 0.157

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.0238

Gnomad OTH exome AF: 0.0342

GnomAD4 exome AF: 0.0315 AC: 46029 AN: 1461696 Hom.: 1613 Cov.: 31 AF XY: 0.0351 AC XY: 25556 AN XY: 727156

Gnomad4 AFR exome AF: 0.0288

Gnomad4 AMR exome AF: 0.0135

Gnomad4 ASJ exome AF: 0.0162

Gnomad4 EAS exome AF: 0.0640

Gnomad4 SAS exome AF: 0.152

Gnomad4 FIN exome AF: 0.0222

Gnomad4 NFE exome AF: 0.0223

Gnomad4 OTH exome AF: 0.0347

GnomAD4 genome AF: 0.0285 AC: 4337 AN: 152188 Hom.: 128 Cov.: 31 AF XY: 0.0310 AC XY: 2307 AN XY: 74412

Gnomad4 AFR AF: 0.0282

Gnomad4 AMR AF: 0.0139

Gnomad4 ASJ AF: 0.0182

Gnomad4 EAS AF: 0.0695

Gnomad4 SAS AF: 0.159

Gnomad4 FIN AF: 0.0197

Gnomad4 NFE AF: 0.0217

Gnomad4 OTH AF: 0.0346

Alfa AF: 0.0240 Hom.: 32

Bravo AF: 0.0253

Asia WGS AF: 0.120 AC: 419 AN: 3478

EpiCase AF: 0.0245

EpiControl AF: 0.0233

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 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. -
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. -

Hereditary spastic paraplegia 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	May 15, 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

Jan 31, 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	-0.50
CADD	Benign	10
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7812319; hg19: chr8-126091094;