rs16900368

chr8-125083261-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014846.4(WASHC5):c.187-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0509 in 1,606,560 control chromosomes in the GnomAD database, including 7,571 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (3120 hom., cov: 32)
  • Exomes 𝑓: 0.043 (4451 hom.)
• Consequence: WASHC5 NM_014846.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0009798
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.43

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 8-125083261-G-A is Benign according to our data. Variant chr8-125083261-G-A is described in ClinVar as [Benign]. Clinvar id is 361735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-125083261-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WASHC5	NM_014846.4	c.187-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000318410.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WASHC5	ENST00000318410.12	c.187-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_014846.4	P1

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19651 AN: 151452 Hom.: 3096 Cov.: 32

Gnomad AFR AF: 0.378

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0523

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.0704

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.0201

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0236

Gnomad OTH AF: 0.112

GnomAD3 exomes AF: 0.0698 AC: 17237 AN: 246930 Hom.: 1732 AF XY: 0.0677 AC XY: 9050 AN XY: 133734

Gnomad AFR exome AF: 0.382

Gnomad AMR exome AF: 0.0346

Gnomad ASJ exome AF: 0.0175

Gnomad EAS exome AF: 0.0772

Gnomad SAS exome AF: 0.161

Gnomad FIN exome AF: 0.0230

Gnomad NFE exome AF: 0.0255

Gnomad OTH exome AF: 0.0501

GnomAD4 exome AF: 0.0427 AC: 62104 AN: 1454990 Hom.: 4451 Cov.: 30 AF XY: 0.0452 AC XY: 32707 AN XY: 723938

Gnomad4 AFR exome AF: 0.394

Gnomad4 AMR exome AF: 0.0374

Gnomad4 ASJ exome AF: 0.0170

Gnomad4 EAS exome AF: 0.0639

Gnomad4 SAS exome AF: 0.155

Gnomad4 FIN exome AF: 0.0221

Gnomad4 NFE exome AF: 0.0234

Gnomad4 OTH exome AF: 0.0613

GnomAD4 genome AF: 0.130 AC: 19721 AN: 151570 Hom.: 3120 Cov.: 32 AF XY: 0.130 AC XY: 9639 AN XY: 74076

Gnomad4 AFR AF: 0.378

Gnomad4 AMR AF: 0.0523

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.0700

Gnomad4 SAS AF: 0.164

Gnomad4 FIN AF: 0.0201

Gnomad4 NFE AF: 0.0236

Gnomad4 OTH AF: 0.110

Alfa AF: 0.0672 Hom.: 651

Bravo AF: 0.139

EpiCase AF: 0.0273

EpiControl AF: 0.0260

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 24, 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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	4.0
Dann	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00098
dbscSNV1_RF	Benign	0.0080
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: rs16900368; hg19: chr8-126095503;