rs1553321237

Positions:

• chr2-32154420-T-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_014946.4(SPAST):​c.1775T>A​(p.Ile592Lys) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I592M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPAST NM_014946.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.65

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 14 ACMG points.

• PM1: In a hotspot region, there are 3 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912
• PP5: Variant 2-32154420-T-A is Pathogenic according to our data. Variant chr2-32154420-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 536446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32154420-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPAST	NM_014946.4	c.1775T>A	p.Ile592Lys	missense_variant	17/17	ENST00000315285.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPAST	ENST00000315285.9	c.1775T>A	p.Ile592Lys	missense_variant	17/17	1	NM_014946.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 07, 2020	PM1, PM2, PM6, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2019	Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31157359) -

Hereditary spastic paraplegia 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 15, 2021	This sequence change replaces isoleucine with lysine at codon 592 of the SPAST protein (p.Ile592Lys). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and lysine. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with hereditary spastic paraplegia (PMID: 31157359, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 536446). This variant is not present in population databases (ExAC no frequency). -
Likely pathogenic, no assertion criteria provided	provider interpretation	Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.92	D;D;.;.;.;.;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	.;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H;H;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.5	D;.;D;.;.;.;.;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;D;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;.;.;.;.;.
Polyphen		1.0	D;D;.;.;.;.;.;.
Vest4		0.72
MutPred		0.59		Loss of stability (P = 0.0035);Loss of stability (P = 0.0035);.;.;.;.;.;.;
MVP		0.94
MPC		2.9
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.98
gMVP		0.95

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: rs1553321237; hg19: chr2-32379489;