rs1191508807

chr2-32137127-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_014946.4(SPAST):c.1432G>A(p.Asp478Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,580 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D478V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SPAST NM_014946.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.03

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_014946.4
• 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.1432G>A	p.Asp478Asn	missense_variant	12/17	ENST00000315285.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPAST	ENST00000315285.9	c.1432G>A	p.Asp478Asn	missense_variant	12/17	1	NM_014946.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251224 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135774

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461580 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

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

Oct 14, 2017

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SPAST-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with asparagine at codon 478 of the SPAST protein (p.Asp478Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;D;.;.;.;.;.;.
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	1.5	L;L;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.6	D;.;D;.;.;.;.;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D;.;D;.;.;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;.;.;.;.;.
Polyphen		0.98	D;D;.;.;.;.;.;.
Vest4		0.51
MutPred		0.55		Loss of catalytic residue at D478 (P = 0.1199);Loss of catalytic residue at D478 (P = 0.1199);.;.;.;.;.;.;
MVP		0.93
MPC		2.1
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.79
gMVP		0.86

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: rs1191508807; hg19: chr2-32362196;