rs864622179

Positions:

• chr2-32144996-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 8.54

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]

ACMG classification

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/exons	MANE	Protein	UniProt
SPAST	NM_014946.4	c.1676G>A	p.Gly559Asp	missense_variant	15/17	ENST00000315285.9	NP_055761.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPAST	ENST00000315285.9	c.1676G>A	p.Gly559Asp	missense_variant	15/17	1	NM_014946.4	ENSP00000320885.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458790 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 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.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 4 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Dec 04, 2024	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 22, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 19, 2023	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 219608). This variant is also known as Gly527Asp, 1583G>A and c.G1801A. 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 not present in population databases (gnomAD no frequency). 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). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 10, 2024	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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2024	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) -

Hereditary spastic paraplegia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;D;.;.;.;.;.;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	M;M;.;.;.;.;.;.
PrimateAI	Pathogenic	0.94	D
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	D
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

Other links and lift over

dbSNP: rs864622179; hg19: chr2-32370065;