2-32063834-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_014946.4(SPAST):c.3G>C(p.Met1?) variant causes a start lost 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPAST NM_014946.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.54

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 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPAST	NM_014946.4	c.3G>C	p.Met1?	start_lost	1/17	ENST00000315285.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPAST	ENST00000315285.9	c.3G>C	p.Met1?	start_lost	1/17	1	NM_014946.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 07, 2023

This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the SPAST mRNA. The next in-frame methionine is located at codon 87. Disruption of the initiator codon has been observed in individual(s) with clinical features of SPAST-related conditions (PMID: 30476002). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts a region of the SPAST protein in which other variant(s) (p.Glu43Gln) have been observed in individuals with SPAST-related conditions (PMID: 16055926). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1917540). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.22	T;T;.;.;.;.
Eigen	Benign	-0.098
Eigen_PC	Benign	-0.023
FATHMM_MKL	Benign	0.65	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-0.69	N;.;N;.;.;.
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;.;D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;.;.
Polyphen		0.077	B;B;.;.;.;.
Vest4		0.94
MutPred		0.99		Gain of catalytic residue at M1 (P = 0.0958);Gain of catalytic residue at M1 (P = 0.0958);Gain of catalytic residue at M1 (P = 0.0958);Gain of catalytic residue at M1 (P = 0.0958);Gain of catalytic residue at M1 (P = 0.0958);Gain of catalytic residue at M1 (P = 0.0958);
MVP		0.98
ClinPred		1.0	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.94
gMVP		0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-32288903;