rs16900368

Variant names:

• chr8-125083261-G-A
• rs16900368
• NM_014846.4:c.187-3C>T

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.0009798
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.43
• Publications: 11 publications found

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]

WASHC5 Gene-Disease associations (from GenCC):

• Ritscher-Schinzel syndrome 1

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• hereditary spastic paraplegia 8

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Ritscher-Schinzel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 361735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
WASHC5	NM_014846.4	c.187-3C>T		splice_region_variant, intron_variant	Intron 2 of 28	ENST00000318410.12	NP_055661.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WASHC5	ENST00000318410.12	c.187-3C>T		splice_region_variant, intron_variant	Intron 2 of 28	1	NM_014846.4	ENSP00000318016.7

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

GnomAD2 exomes AF: 0.0698 AC: 17237 AN: 246930 AF XY: 0.0677

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 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

African (AFR) AF: 0.394 AC: 13003 AN: 33010

American (AMR) AF: 0.0374 AC: 1632 AN: 43654

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 440 AN: 25946

East Asian (EAS) AF: 0.0639 AC: 2528 AN: 39540

South Asian (SAS) AF: 0.155 AC: 13209 AN: 85222

European-Finnish (FIN) AF: 0.0221 AC: 1177 AN: 53202

Middle Eastern (MID) AF: 0.0805 AC: 462 AN: 5738

European-Non Finnish (NFE) AF: 0.0234 AC: 25969 AN: 1108624

Other (OTH) AF: 0.0613 AC: 3684 AN: 60054

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

African (AFR) AF: 0.378 AC: 15645 AN: 41348

American (AMR) AF: 0.0523 AC: 798 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3464

East Asian (EAS) AF: 0.0700 AC: 362 AN: 5174

South Asian (SAS) AF: 0.164 AC: 789 AN: 4822

European-Finnish (FIN) AF: 0.0201 AC: 208 AN: 10332

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0236 AC: 1602 AN: 67860

Other (OTH) AF: 0.110 AC: 232 AN: 2102

Alfa AF: 0.0761 Hom.: 783

Bravo AF: 0.139

EpiCase AF: 0.0273

EpiControl AF: 0.0260

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 8 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 27, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Feb 24, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.0
DANN	Benign	0.54
PhyloP100		1.4
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16900368; hg19: chr8-126095503; COSMIC: COSV107384460;