2-32136933-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_014946.4(SPAST):c.1378C>T(p.Arg460Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R460S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SPAST
NM_014946.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 3.42

Variant links:

Genes affected

SPAST (HGNC:11233): (spastin) This gene encodes a member of the AAA (ATPases associated with a variety of cellular activities) protein family. Members of this protein family share an ATPase domain and have roles in diverse cellular processes including membrane trafficking, intracellular motility, organelle biogenesis, protein folding, and proteolysis. The use of alternative translational initiation sites in this gene results in a single transcript variant that can produce isoforms that differ in the length of their N-terminus and which thereby differ in the efficiency of their export from the nucleus to the cytoplasm. In addition, alternative splicing results in multiple transcript variants that encode isoforms that differ in other protein regions as well. One isoform of this gene has been shown to be a microtubule-severing enzyme that regulates microtubule abundance, mobility, and plus-end distribution. Mutations in this gene cause the most frequent form of autosomal dominant spastic paraplegia 4. [provided by RefSeq, May 2018]

SPAST links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-32136933-C-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 2-32136933-C-T is Pathogenic according to our data. Variant chr2-32136933-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 240948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32136933-C-T is described in UniProt as null. Variant chr2-32136933-C-T is described in Lovd as [Pathogenic]. Variant chr2-32136933-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPAST	NM_014946.4 link	c.1378C>T	p.Arg460Cys	missense_variant	Exon 11 of 17	ENST00000315285.9	NP_055761.2	Q9UBP0-1E5KRP5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPAST	ENST00000315285.9 link	c.1378C>T	p.Arg460Cys	missense_variant	Exon 11 of 17	1	NM_014946.4	ENSP00000320885.3		Q9UBP0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461316

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727006

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Mar 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 29, 2018

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not found in the total gnomAD dataset, and the data is high quality (0/276546 chr). Statistically enriched in patients compared to ethnically matched controls. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Two other pathogenic or likely pathogenic variants affect the same amino acid. Co-occurs with otherwise positive results less than expected. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 21, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP2, PP3, PM1, PM2, PS4 -

Hereditary spastic paraplegia 4

Pathogenic:6

Feb 03, 2023

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS4 strong, PM1 moderated, PM2 moderated, PP1 strong, PP3 supporting -

Oct 19, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and dominant negative are known mechanisms of disease for this gene and are associated with autosomal dominant spastic paraplegia 4 (MIM#182601). Multiple loss of function variants have been reported, while a dominant negative mechanism has been stipulated for a small number of missense variants (ClinVar; PMID: 30006150). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. The penetrance is mostly complete and is lower in females (PMID: 30476002). (I) 0115 - Variants in this gene are known to have variable expressivity. Age at onset of symptoms ranges from infancy to the eighth decade and there is significant intrafamilial clinical variability (PMID: 30476002). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). It is also located in the annotated AAA domain (PDB), where most missense variants reported are located (PMID: 30476002). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in many unrelated families with hereditary spastic paraplegia (ClinVar, PMIDs: 30778698, 29246610, 27688599, 28572275). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Paris Brain Institute, Inserm - ICM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 460 of the SPAST protein (p.Arg460Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 15248095, 15482961, 16055926, 16832076, 17594340, 18701882, 20718791, 22960362, 24451228, 25658484). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this SPAST variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 3,690 individuals referred to our laboratory for SPAST testing. ClinVar contains an entry for this variant (Variation ID: 240948). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SPAST protein function with a positive predictive value of 80%. This missense change is located in a region of the SPAST protein in which a significant number of missense variants have been reported (PMID: 11809724). These observations suggest that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic. -

May 23, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 09, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SPAST c.1378C>T (p.Arg460Cys) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of the encoded protein sequence. This alters a well-conserved residue in which several missense changes have been found in association with Spastic paraplegia (HGMD), two of which (p.Arg460Leu, p.Arg460His) have been classified as pathogenic or likely pathogenic by ClinVar submitters. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251056 control chromosomes (gnomAD). c.1378C>T has been reported in the literature in multiple individuals affected with Spastic Paraplegia 4, Autosomal Dominant (e.g. Falco_2004, Burguez_2017, Mereaux_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 15482961, 29246610, 34983064). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary spastic paraplegia

Pathogenic:1

May 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;D;.;.;.;.;.;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

.;D;D;.;D;D;D;D

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.1

M;M;.;.;.;.;.;.

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-8.0

D;.;D;.;.;.;.;.

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;.;D;.;.;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;.;.;.;.;.

Polyphen

1.0

D;D;.;.;.;.;.;.

Vest4

0.95

MutPred

0.96

Gain of catalytic residue at L461 (P = 0.0116);Gain of catalytic residue at L461 (P = 0.0116);.;.;.;.;.;.;

MVP

0.98

MPC

1.6

ClinPred

1.0

GERP RS

5.6

Varity_R

0.96

gMVP

0.93

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