rs587777757

Positions:

• chr2-32128450-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The ENST00000315285.9(SPAST):​c.1216A>G​(p.Ile406Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,338 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I406T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SPAST ENST00000315285.9 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 8.25

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 16 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, 6 uncertain in ENST00000315285.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-32128451-T-C is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872
• PP5: Variant 2-32128450-A-G is Pathogenic according to our data. Variant chr2-32128450-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 5675.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.1216A>G	p.Ile406Val	missense_variant	9/17	ENST00000315285.9	NP_055761.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPAST	ENST00000315285.9	c.1216A>G	p.Ile406Val	missense_variant	9/17	1	NM_014946.4	ENSP00000320885	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460338 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 726588

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 4 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 19, 2022	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 406 of the SPAST protein (p.Ile406Val). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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: 5675). This missense change has been observed in individual(s) with hereditary spastic paraplegia and was observed to be de novo in at least one individual (PMID: 16476945, 16682546, 16832076, 17971434, 18701882, 19423133). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 14, 2006	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2024	Identified in patients with HSP in published literature, but segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members (PMID: 16682546, 19423133, 20562464); Published functional studies demonstrate damaging effects, including aberrant in-frame splicing, destabilization of mutated transcript, and deficient in microtubule-severing activity (PMID: 16476945); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 30476002, 16832076, 20562464, 19423133, 16476945, 31157359, 16055926, 34758253, 21139634, 26094131, 31594988, 34983064, 16682546) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 16, 2020	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant appears to occur de novo in one individual with clinical features associated with this gene. Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. This variant resulted in a 30-bp deletion when expressed in a cell line. However, only 20% of transcript was affected and it is unclear if this is sufficient aberrant transcript to cause disease (PMID 16476945). Computational tools predict that this variant is damaging. The variant is located in a region that is considered important for protein function and/or structure. -

Hereditary spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 15, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;D;.;.;.;.;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D;D;.;D;D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	-0.42	N;N;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.97	N;.;N;.;.;.;.;.
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	D;.;T;.;.;.;.;.
Sift4G	Benign	0.083	T;T;T;.;.;.;.;.
Polyphen		0.86	P;P;.;.;.;.;.;.
Vest4		0.80
MutPred		0.90		Loss of catalytic residue at L411 (P = 0.0994);Loss of catalytic residue at L411 (P = 0.0994);.;.;.;.;.;.;
MVP		0.94
MPC		2.0
ClinPred		0.96	D
GERP RS		5.9
Varity_R		0.66
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.95		Position offset: -1
DS_DL_spliceai		0.47		Position offset: 29

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587777757; hg19: chr2-32353519;