rs373599521

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014846.4(WASHC5):c.3296T>C(p.Ile1099Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

WASHC5
NM_014846.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.51

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WASHC5	NM_014846.4 link	c.3296T>C	p.Ile1099Thr	missense_variant	Exon 27 of 29	ENST00000318410.12	NP_055661.3	Q12768
WASHC5	NM_001330609.2 link	c.2852T>C	p.Ile951Thr	missense_variant	Exon 26 of 28		NP_001317538.1	E7EQI7
WASHC5	XM_047422502.1 link	c.3296T>C	p.Ile1099Thr	missense_variant	Exon 28 of 30		XP_047278458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
WASHC5	ENST00000318410.12 link	c.3296T>C	p.Ile1099Thr	missense_variant	Exon 27 of 29	1	NM_014846.4	ENSP00000318016.7	Q12768
WASHC5	ENST00000517845.5 link	c.2852T>C	p.Ile951Thr	missense_variant	Exon 25 of 27	2		ENSP00000429676.1	E7EQI7
WASHC5	ENST00000519042.2 link	n.435T>C		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251244

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000650

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000791

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000773

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Feb 21, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS2, PP3 -

Apr 21, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia

Uncertain:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ritscher-Schinzel syndrome;C1863704:Hereditary spastic paraplegia 8

Uncertain:1

Jan 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1099 of the KIAA0196 protein (p.Ile1099Thr). This variant is present in population databases (rs373599521, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with KIAA0196-related conditions. ClinVar contains an entry for this variant (Variation ID: 196031). 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 KIAA0196 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

0.098

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;.

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.69

D;D

MetaSVM

Uncertain

0.13

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.6

D;N

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

0.32

B;.

Vest4

0.71

MVP

0.88

MPC

0.37

ClinPred

0.35

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.28

gMVP

0.64

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over