rs1553316799

Positions:

• chr2-32126952-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_014946.4(SPAST):​c.1103T>C​(p.Phe368Ser) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F368L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SPAST NM_014946.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.47

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 2-32126952-T-C is Pathogenic according to our data. Variant chr2-32126952-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 536436.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.1103T>C	p.Phe368Ser	missense_variant	8/17	ENST00000315285.9	NP_055761.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPAST	ENST00000315285.9	c.1103T>C	p.Phe368Ser	missense_variant	8/17	1	NM_014946.4	ENSP00000320885.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 4 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 27, 2022	Variant summary: SPAST c.1103T>C (p.Phe368Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250952 control chromosomes. c.1103T>C has been reported in the literature in individuals affected with hereditary spastic paraparesis and ataxic disorder (McDermott_2006, Ngo_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 17, 2017	For these reasons, this variant has been classified as Pathogenic. Different missense substitutions at this codon (p.Phe368Val and p.Phe368Leu) have been reported in affected individuals (PMID: 28572275, 21546041). This suggests that the phenylalanine residue is critical for SPAST protein function. 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 reported in multiple individuals affected with hereditary spastic paraplegia (PMID: 16832076). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with serine at codon 368 of the SPAST protein (p.Phe368Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.80	D;D;.;.;.;.;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M;M;.;.;.;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.7	D;.;D;.;.;.;.;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;D;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;.;.;.;.;.
Polyphen		1.0	D;D;.;.;.;.;.;.
Vest4		0.99
MutPred		0.96		Gain of disorder (P = 0.002);Gain of disorder (P = 0.002);.;.;.;.;.;.;
MVP		0.98
MPC		2.9
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.97
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1553316799; hg19: chr2-32352021;