2-32127013-G-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_014946.4(SPAST):c.1164G>T(p.Lys388Asn) variant causes a missense change involving the alteration of a non-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 nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K388R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SPAST NM_014946.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.235

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 22 ACMG points.

• PS1: Transcript NM_014946.4 (SPAST) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 1454039
• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr2-32127012-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1442734.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 2-32127013-G-T is Pathogenic according to our data. Variant chr2-32127013-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 450255.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.1164G>T	p.Lys388Asn	missense_variant	8/17	ENST00000315285.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPAST	ENST00000315285.9	c.1164G>T	p.Lys388Asn	missense_variant	8/17	1	NM_014946.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 06, 2017

The K388N variant in the SPAST gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The K388N variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The K388N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a conserved position within the ATPase domain. Missense variants in nearby residues (G385W, G385E, N386S, N386K, M390V, M390I, L391Q, L391P) have been reported in the Human Gene Mutation Database in association with spastic paraplegia (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret K388N as a pathogenic variant. -

Hereditary spastic paraplegia 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 12, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Lys388 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10699187, 20665701). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 450255). This missense change has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 30476002; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 388 of the SPAST protein (p.Lys388Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;.;.;.;.;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.7	H;H;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.8	D;.;D;.;.;.;.;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D;.;D;.;.;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;.;.;.;.;.
Polyphen		1.0	D;D;.;.;.;.;.;.
Vest4		0.96
MutPred		0.92		Loss of methylation at K388 (P = 0.0057);Loss of methylation at K388 (P = 0.0057);.;.;.;.;.;.;
MVP		0.97
MPC		2.4
ClinPred		1.0	D
GERP RS		-0.42
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1553316838; hg19: chr2-32352082;