rs864622179

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_014946.4(SPAST):c.1676G>A(p.Gly559Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SPAST
NM_014946.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 8.54

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.938

PP5

Variant 2-32144996-G-A is Pathogenic according to our data. Variant chr2-32144996-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 219608.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.1676G>A	p.Gly559Asp	missense_variant	Exon 15 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.1676G>A	p.Gly559Asp	missense_variant	Exon 15 of 17	1	NM_014946.4	ENSP00000320885.3		Q9UBP0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1458790

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725716

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 4

Pathogenic:3

Jul 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 559 of the SPAST protein (p.Gly559Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 11087788, 11843700, 15248095, 17598600, 20718791, 22960362; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as Gly527Asp, 1583G>A and c.G1801A. ClinVar contains an entry for this variant (Variation ID: 219608). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SPAST protein function. For these reasons, this variant has been classified as Pathogenic. -

May 22, 2024

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.1676G>A (p.Gly559Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249424 control chromosomes. c.1676G>A has been reported in the literature in multiple individuals affected with utosomal dominant Hereditary Spastic Paraplegia (example, Hentati_2000, Meijer_2002, Meijer_2007, Svenson_2004). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11087788, 11843700, 17598600, 15248095). ClinVar contains an entry for this variant (Variation ID: 219608). Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 04, 2024

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as likely pathogenic for Spastic paraplegia 4, autosomal dominant. This missense change is absent from large population cohorts (gnomAD v4.1.0; PM2_supporting); it has been observed in multiple unrelated patients (PMID: 11087788, 11843700, 17598600, 20718791; PS4_moderate); computational evidence support a damaging effect on gene or gene product (PP3_moderate REVEL 0.894); this change affects an amino acid residue where a different missense change has been determined to be pathogenic/likely pathogenic (p.Gly559Arg PMID: 22960362, 27688599; PM5_moderate). -

not provided

Pathogenic:2

Jan 30, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported multiple times in individuals with spastic paraplegia (PMID: 20718791, 11087788, 11843700, 22960362); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11087788, 17598600, 11843700, 31285604, 22960362, 15248095, 21139634, 26094131, 35487127, 20718791) -

Apr 10, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. In some published literature, this variant is referred to as 1801G>A and 1583G>A (Gly527Asp). -

Hereditary spastic paraplegia

Pathogenic:1

Nov 09, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

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

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.94

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.4

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

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-4.7

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

REVEL

Pathogenic

0.89

Sift

Uncertain

0.016

D;.;T;.;.;.;.;.

Sift4G

Benign

0.24

T;T;T;.;.;.;.;.

Polyphen

0.99

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

Vest4

0.94

MutPred

0.80

Loss of helix (P = 0.0138);Loss of helix (P = 0.0138);.;.;.;.;.;.;

MVP

0.97

MPC

2.5

ClinPred

0.99

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.89

gMVP

0.96

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