Genetic Variant NM_014846.4:c.867A>C (chr8-125075109-T-G) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_014846.4(WASHC5):c.867A>C(p.Val289Val) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000898 in 1,556,028 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0045 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 5 hom. )

Consequence

WASHC5
NM_014846.4 splice_region, synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.377

Publications

0 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 8-125075109-T-G is Benign according to our data. Variant chr8-125075109-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 219414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.377 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0045 (686/152284) while in subpopulation AFR AF = 0.0161 (669/41578). AF 95% confidence interval is 0.0151. There are 6 homozygotes in GnomAd4. There are 296 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014846.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WASHC5	NM_014846.4	MANE Select	c.867A>C	p.Val289Val	splice_region synonymous	Exon 8 of 29	NP_055661.3
	WASHC5	NM_001330609.2		c.423A>C	p.Val141Val	splice_region synonymous	Exon 7 of 28	NP_001317538.1	E7EQI7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WASHC5	ENST00000318410.12	TSL:1 MANE Select	c.867A>C	p.Val289Val	splice_region synonymous	Exon 8 of 29	ENSP00000318016.7	Q12768
WASHC5	ENST00000920325.1		c.867A>C	p.Val289Val	splice_region synonymous	Exon 8 of 29	ENSP00000590384.1
WASHC5	ENST00000890504.1		c.867A>C	p.Val289Val	splice_region synonymous	Exon 9 of 30	ENSP00000560563.1

Frequencies

GnomAD3 genomes

AF:

0.00451

AC:

686

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0161

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00122

AC:

305

AN:

251020

AF XY:

0.000825

show subpopulations

Gnomad AFR exome

AF:

0.0164

Gnomad AMR exome

AF:

0.000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000507

AC:

712

AN:

1403744

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

311

AN XY:

701790

show subpopulations

African (AFR)

AF:

0.0181

AC:

586

AN:

32288

American (AMR)

AF:

0.000851

AC:

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25736

East Asian (EAS)

AF:

0.00

AC:

AN:

39342

South Asian (SAS)

AF:

0.0000470

AC:

AN:

85088

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53272

Middle Eastern (MID)

AF:

0.00124

AC:

AN:

5646

European-Non Finnish (NFE)

AF:

0.00000472

AC:

AN:

1059242

Other (OTH)

AF:

0.00123

AC:

AN:

58470

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

105

140

175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00450

AC:

686

AN:

152284

Hom.:

Cov.:

AF XY:

0.00398

AC XY:

296

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0161

AC:

669

AN:

41578

American (AMR)

AF:

0.000981

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68002

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

110

146

183

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00207

Hom.:

Bravo

AF:

0.00527

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 8 (1)

Hereditary spastic paraplegia 8;C4551776:Ritscher-Schinzel syndrome 1 (1)

not provided (1)

not specified (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

6.1

(source)

DANN

Benign

0.55

PhyloP100

-0.38

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over