dbSNP rs72720524: WASHC5:p.Pro216Leu (chr8-125078802-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3BP4_StrongBP6BS1BS2

The NM_014846.4(WASHC5):c.647C>T(p.Pro216Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,613,926 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

WASHC5
NM_014846.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 9.80

Publications

7 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 -12 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.058928013).

BP6

Variant 8-125078802-G-A is Benign according to our data. Variant chr8-125078802-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 431857.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000933 (142/152200) while in subpopulation NFE AF = 0.00134 (91/68002). AF 95% confidence interval is 0.00112. There are 0 homozygotes in GnomAd4. There are 73 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 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.647C>T	p.Pro216Leu	missense	Exon 6 of 29	NP_055661.3
	WASHC5	NM_001330609.2		c.203C>T	p.Pro68Leu	missense	Exon 5 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.647C>T	p.Pro216Leu	missense	Exon 6 of 29	ENSP00000318016.7	Q12768
WASHC5	ENST00000920325.1		c.647C>T	p.Pro216Leu	missense	Exon 6 of 29	ENSP00000590384.1
WASHC5	ENST00000890504.1		c.647C>T	p.Pro216Leu	missense	Exon 7 of 30	ENSP00000560563.1

Frequencies

GnomAD3 genomes

AF:

0.000934

AC:

142

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00134

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00108

AC:

272

AN:

251368

AF XY:

0.00111

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00393

Gnomad NFE exome

AF:

0.00154

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.00113

AC:

1654

AN:

1461726

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

791

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33474

American (AMR)

AF:

0.0000447

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00369

AC:

197

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00125

AC:

1394

AN:

1111888

Other (OTH)

AF:

0.000911

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

163

245

326

408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

156

208

260

<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:

0.000933

AC:

142

AN:

152200

Hom.:

Cov.:

AF XY:

0.000981

AC XY:

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41518

American (AMR)

AF:

0.000131

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00377

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00134

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00138

Hom.:

Bravo

AF:

0.000808

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00122

AC:

148

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.000830

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Hereditary spastic paraplegia 8 (1)

not specified (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.049

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.059

MetaSVM

Uncertain

0.75

PhyloP100

9.8

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-6.1

REVEL

Pathogenic

0.81

Sift

Uncertain

0.012

Sift4G

Uncertain

0.055

Polyphen

1.0

Vest4

0.88

MVP

0.96

MPC

0.66

ClinPred

0.13

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.50

gMVP

0.73

Mutation Taster

=16/84

disease causing

(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

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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