8-125078852-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.638

Publications

9 publications found

Variant links:

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

WASHC5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 129377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
WASHC5	NM_014846.4 link	c.597A>G	p.Pro199Pro	synonymous_variant	Exon 6 of 29	ENST00000318410.12	NP_055661.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
WASHC5	ENST00000318410.12 link	c.597A>G	p.Pro199Pro	synonymous_variant	Exon 6 of 29	1	NM_014846.4	ENSP00000318016.7
WASHC5	ENST00000517845.5 link	c.153A>G	p.Pro51Pro	synonymous_variant	Exon 4 of 27	2		ENSP00000429676.1
WASHC5	ENST00000523297.5 link	c.153A>G	p.Pro51Pro	synonymous_variant	Exon 5 of 7	3		ENSP00000427946.1

Frequencies

GnomAD3 genomes

AF:

0.0285

AC:

4341

AN:

152070

Hom.:

128

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0425

AC:

10682

AN:

251400

AF XY:

0.0470

show subpopulations

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 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.:

AF XY:

0.0351

AC XY:

25556

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.0288

AC:

965

AN:

33478

American (AMR)

AF:

0.0135

AC:

604

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0162

AC:

424

AN:

26132

East Asian (EAS)

AF:

0.0640

AC:

2539

AN:

39690

South Asian (SAS)

AF:

0.152

AC:

13115

AN:

86250

European-Finnish (FIN)

AF:

0.0222

AC:

1185

AN:

53418

Middle Eastern (MID)

AF:

0.0558

AC:

322

AN:

5768

European-Non Finnish (NFE)

AF:

0.0223

AC:

24781

AN:

1111852

Other (OTH)

AF:

0.0347

AC:

2094

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

2215

4430

6646

8861

11076

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1048

2096

3144

4192

5240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0285

AC:

4337

AN:

152188

Hom.:

128

Cov.:

AF XY:

0.0310

AC XY:

2307

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.0282

AC:

1172

AN:

41520

American (AMR)

AF:

0.0139

AC:

212

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0182

AC:

AN:

3470

East Asian (EAS)

AF:

0.0695

AC:

359

AN:

5166

South Asian (SAS)

AF:

0.159

AC:

765

AN:

4816

European-Finnish (FIN)

AF:

0.0197

AC:

209

AN:

10614

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0217

AC:

1473

AN:

68000

Other (OTH)

AF:

0.0346

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

192

384

576

768

960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0249

Hom.:

106

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

LINK: link

Submissions by phenotype

not specified

Benign:2

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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.

Apr 04, 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.

Hereditary spastic paraplegia 8

Benign:2

Jan 12, 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.

May 15, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary spastic paraplegia

Benign:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

-0.50

CADD

Benign

(source)

DANN

Benign

0.66

PhyloP100

0.64

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over