8-125043833-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014846.4(WASHC5):ā€‹c.2842A>Gā€‹(p.Ile948Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000311 in 1,607,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

WASHC5
NM_014846.4 missense

Scores

1
3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.21
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-AS1 (HGNC:43440): (WASHC5 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.16233554).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WASHC5NM_014846.4 linkuse as main transcriptc.2842A>G p.Ile948Val missense_variant 23/29 ENST00000318410.12 NP_055661.3
WASHC5-AS1NR_170219.1 linkuse as main transcriptn.97-666T>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WASHC5ENST00000318410.12 linkuse as main transcriptc.2842A>G p.Ile948Val missense_variant 23/291 NM_014846.4 ENSP00000318016 P1
WASHC5-AS1ENST00000519140.1 linkuse as main transcriptn.97-666T>C intron_variant, non_coding_transcript_variant 4
WASHC5ENST00000517845.5 linkuse as main transcriptc.2398A>G p.Ile800Val missense_variant 21/272 ENSP00000429676

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152254
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251144
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135734
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000272
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000275
AC:
4
AN:
1455176
Hom.:
0
Cov.:
29
AF XY:
0.00000276
AC XY:
2
AN XY:
724380
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152254
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74386
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000540
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Ritscher-Schinzel syndrome;C1863704:Hereditary spastic paraplegia 8 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 06, 2024This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 948 of the WASHC5 protein (p.Ile948Val). This variant is present in population databases (rs759801315, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with WASHC5-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt WASHC5 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.064
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.11
CADD
Benign
19
DANN
Benign
0.92
DEOGEN2
Benign
0.29
T;.
Eigen
Benign
-0.18
Eigen_PC
Benign
0.031
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.16
T;T
MetaSVM
Benign
-0.51
T
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
-0.18
N;N
REVEL
Uncertain
0.38
Sift
Benign
0.88
T;T
Sift4G
Benign
0.92
T;T
Polyphen
0.058
B;B
Vest4
0.39
MutPred
0.61
Gain of MoRF binding (P = 0.1235);.;
MVP
0.66
MPC
0.22
ClinPred
0.18
T
GERP RS
5.3
Varity_R
0.070
gMVP
0.34

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs759801315; hg19: chr8-126056075; API