rs797044850

chr2-32127017-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_014946.4(SPAST):c.1168A>G(p.Met390Val) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M390I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SPAST NM_014946.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.64

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 18 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr2-32127019-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 430448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 2-32127017-A-G is Pathogenic according to our data. Variant chr2-32127017-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 208644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPAST	NM_014946.4	c.1168A>G	p.Met390Val	missense_variant	8/17	ENST00000315285.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPAST	ENST00000315285.9	c.1168A>G	p.Met390Val	missense_variant	8/17	1	NM_014946.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2017	The M390V variant in the SPAST gene has been reported previously in association with childhood onset hereditary spastic paraplegia, including in a family where the variant segregated with disease in four affected family members across two generations (Tang et al., 2004; Alvarez et al., 2010; Park et al., 2015). The M390V variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M390V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position, within the ATPase domain, that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret M390V as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -

Hereditary spastic paraplegia 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 23, 2020	In summary, this is a rare missense variant that is absent from the general population and reported to co-segregate with disease in two independent families. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases and has been reported in patients with hereditary spastic paraplegia (HSP). In one family, this variant co-segregated with HSP in 4 individuals and was absent from 1 tested individual without disease (PMID: 14732620). In a second family, this variant was confirmed to be de novo in a young child with apparently sporadic HSP (PMID: 20932283). This sequence change replaces methionine with valine at codon 390 of the SPAST protein (p.Met390Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 15, 2014

The c.1168A>G (p.M390V) alteration is located in exon 8 (coding exon 8) of the SPAST gene. This alteration results from a A to G substitution at nucleotide position 1168, causing the methionine (M) at amino acid position 390 to be replaced by a valine (V). The alteration is not observed in healthy cohorts:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the SPAST c.1168A>G alteration was not observed among 6,503 individuals tested. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP)._x000D_ Though some variants may appear to be rare due to database-specific ethnic underrepresentation, rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012). IF USED, PULL THESE INTO REFERENCES:_x000D_ Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. The amino acid change has been observed in affected individuals: _x000D_ This amino acid alteration was reported in several members of a Chinese family with HSP (Tang, 2004). Both pure and complicated HSP patients were seen in this family, with their clinical features including an early age of onset (mean 4.5 years), cognitive deficit, ataxia, epilepsy, and amyotrophy of the lower extremities. This alteration was also seen in de novo form in a Spanish patient with sporadic complicated HSP (Álvarez, 2010). The altered amino acid is conserved throughout evolution:_x000D_ The p.M390 amino acid position is completely conserved in available vertebrate species. The amino acid is located in a functionally important protein domain:_x000D_ The p.M390V amino acid is located in the AAA-ATPase domain of the spastin protein. The highly-conserved AAA cassette contains Walker A and B motifs (sites of ATP binding and ATPase activity), a helix-loop-helix dimerization domain, and a leucine zipper motif (Svenson, 2001). Most mutations in SPG4 affect this domain, and are associated with a trend towards earlier disease onset (Lourerio, 2013). The alteration is predicted deleterious by in silico models:_x000D_ The p.M390V alteration is predicted to be possibly damaging by Polyphen and deleterious by SIFT in silico analyses. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;D;.;.;.;.;.;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.3	M;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.5	N;.;N;.;.;.;.;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0070	D;.;D;.;.;.;.;.
Sift4G	Uncertain	0.012	D;D;D;.;.;.;.;.
Polyphen		0.80	P;P;.;.;.;.;.;.
Vest4		0.96
MutPred		0.89		Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);.;.;.;.;.;.;
MVP		0.99
MPC		2.0
ClinPred		0.95	D
GERP RS		5.7
Varity_R		0.91
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs797044850; hg19: chr2-32352086;