NM_014946.4:c.1291C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_014946.4(SPAST):c.1291C>T(p.Arg431*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SPAST
NM_014946.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11O:2

Conservation

PhyloP100: 2.17

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

hereditary spastic paraplegia 4
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, Genomics England PanelApp, Ambry Genetics
Charlevoix-Saguenay spastic ataxia
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
neurodevelopmental disorder
Inheritance: AD Classification: STRONG Submitted by: G2P
SPAST-related motor disorder
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics

SPAST links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-32136608-C-T is Pathogenic according to our data. Variant chr2-32136608-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 188179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPAST	NM_014946.4 link	c.1291C>T	p.Arg431*	stop_gained	Exon 10 of 17	ENST00000315285.9	NP_055761.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPAST	ENST00000315285.9 link	c.1291C>T	p.Arg431*	stop_gained	Exon 10 of 17	1	NM_014946.4	ENSP00000320885.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461310

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727002

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111596

Other (OTH)

AF:

0.00

AC:

AN:

60354

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 4

Pathogenic:6Other:2

GenomeConnect - Invitae Patient Insights Network

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Pathogenic and reported on 08-30-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Aug 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg431*) in the SPAST gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPAST are known to be pathogenic (PMID: 20932283). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia (PMID: 10699187, 18701882, 20718791, 25454648, 29980238). ClinVar contains an entry for this variant (Variation ID: 188179). For these reasons, this variant has been classified as Pathogenic.

Feb 02, 2022

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_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss-of-function are known mechanisms of disease for this gene and are associated with 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, but this is age-dependant and only a small proportion of individuals remain asymptomatic (PMID: 30476002). (I) 0115 - Variants in this gene are known to have variable expressivity, with variable age of onset and disease severity (PMID: 30476002). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic and observed in individuals with hereditary spastic paraplegia (HSP) (PMID: 31751864, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and observed in individuals with HSP (ClinVar, PMID: 31751864). (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

GenomeConnect - Brain Gene Registry

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Pathogenic and reported on 02-23-2021 by lab or GTR ID 239772. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

Jan 27, 2022

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 01, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change in SPAST is a nonsense variant predicted to cause a premature stop codon, p.(Arg431*), in biologically relevant exon 10/21 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.00009% (1/1,111,596 alleles) in the European (non-Finnish) population, which is consistent with spastic paraplegia. This variant has been reported in multiple individuals with hereditary spastic paraplegia (PMID: 31751864, 31594988, 37144097). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM2_Supporting, PS4_Moderate

Jun 01, 2022

Solve-RD Consortium

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:provider interpretation

Variant confirmed as disease-causing by referring clinical team

not provided

Pathogenic:4

May 12, 2023

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene.

Aug 30, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20718791, 34782662, 25525159, 10699187, 29980238, 26208798, 22960362, 27084228, 25454648, 26671083, 19423133, 30489674, 27334366, 15841487, 20559269, 31227335, 32213280, 31594988, 23252998)

Apr 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary spastic paraplegia

Pathogenic:1

Apr 01, 2018

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

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;.;.;.;.;.;.;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.0

.;.;.;.;.;.;.;.

MetaRNN

Benign

0.0

.;.;.;.;.;.;.;.

MutationAssessor

Benign

0.0

.;.;.;.;.;.;.;.

PhyloP100

2.2

PROVEAN

Benign

0.0

.;.;.;.;.;.;.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;.;.;.;.;.;.

Sift4G

Pathogenic

0.0

.;.;.;.;.;.;.;.

Vest4

0.95

GERP RS

3.6

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over