2-32128430-C-G

Variant names:

• chr2-32128430-C-G
• rs1553317025
• NM_014946.4:c.1196C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_014946.4(SPAST):​c.1196C>G​(p.Ser399Trp) variant causes a missense change. 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S399L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPAST NM_014946.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.99
• Publications: 0 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_014946.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-32128430-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 448442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 148 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. Gene score misZ: 1.2438 (below the threshold of 3.09). Trascript score misZ: 0.22274 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary spastic paraplegia 4, SPAST-related motor disorder, Charlevoix-Saguenay spastic ataxia, neurodevelopmental disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• PP5: Variant 2-32128430-C-G is Pathogenic according to our data. Variant chr2-32128430-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 468561.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPAST	NM_014946.4	c.1196C>G	p.Ser399Trp	missense_variant	Exon 9 of 17	ENST00000315285.9	NP_055761.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPAST	ENST00000315285.9	c.1196C>G	p.Ser399Trp	missense_variant	Exon 9 of 17	1	NM_014946.4	ENSP00000320885.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 4 Pathogenic:1

Jan 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 399 of the SPAST protein (p.Ser399Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 33179235; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 468561). 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 expected to disrupt SPAST protein function with a positive predictive value of 80%. This variant disrupts the p.Ser399 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11843700, 16832076, 19875132, 22960362, 29980238). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;D;.;.;.;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;D;.;D;D;D;D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.3	M;M;.;.;.;.;.;.
PhyloP100		7.0
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.5	D;.;D;.;.;.;.;.
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0020	D;.;D;.;.;.;.;.
Sift4G	Uncertain	0.0020	D;D;D;.;.;.;.;.
Polyphen		1.0	D;D;.;.;.;.;.;.
Vest4		0.83
MutPred		0.78		Loss of disorder (P = 0.0461);Loss of disorder (P = 0.0461);.;.;.;.;.;.;
MVP		0.92
MPC		2.6
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.92
gMVP		0.98
Mutation Taster		=24/76	disease causing

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

Other links and lift over

dbSNP: rs1553317025; hg19: chr2-32353499;