rs1553319075

Variant names:

• chr2-32141904-G-C
• rs1553319075
• NM_014946.4:c.1494G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Moderate

The NM_014946.4(SPAST):​c.1494G>C​(p.Arg498Ser) variant causes a missense, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R498K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPAST NM_014946.4 missense, splice_region
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.09
• Publications: 2 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 10 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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 chr2-32137188-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2684011.
• 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: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 2-32141904-G-C is Pathogenic according to our data. Variant chr2-32141904-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 536434.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.1494G>C	p.Arg498Ser	missense_variant, splice_region_variant	Exon 13 of 17	ENST00000315285.9	NP_055761.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPAST	ENST00000315285.9	c.1494G>C	p.Arg498Ser	missense_variant, splice_region_variant	Exon 13 of 17	1	NM_014946.4	ENSP00000320885.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Nov 13, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts the p.Arg498 amino acid residue in SPAST. Other variants that disrupt this residue have been observed in individuals with SPAST-related disease (PMID: 16832076, 20932283, 28572275), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine with serine at codon 498 of the SPAST protein (p.Arg498Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with spastic paraplegia, including at least one individual in whom this variant was found to be de novo (PMID: 26671083, Invitae). ClinVar contains an entry for this variant (Variation ID: 536434). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D;.;.;.;.;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	.;D;D;.;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.2	M;M;.;.;.;.;.;.
PhyloP100		3.1
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.0	D;.;D;.;.;.;.;.
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;.;D;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;.;.;.;.;.
Polyphen		1.0	D;D;.;.;.;.;.;.
Vest4		0.98
MutPred		0.94		Loss of MoRF binding (P = 0.0235);Loss of MoRF binding (P = 0.0235);.;.;.;.;.;.;
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.96
gMVP		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.080		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: rs1553319075; hg19: chr2-32366973;