2-32063851-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014946.4(SPAST):c.20G>T(p.Arg7Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000028 in 1,429,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R7P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: SPAST NM_014946.4 missense
• 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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34162474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPAST	NM_014946.4	c.20G>T	p.Arg7Leu	missense_variant	1/17	ENST00000315285.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPAST	ENST00000315285.9	c.20G>T	p.Arg7Leu	missense_variant	1/17	1	NM_014946.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000100 AC: 2 AN: 199314 Hom.: 0 AF XY: 0.0000182 AC XY: 2 AN XY: 109748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000649

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000111

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000280 AC: 4 AN: 1429578 Hom.: 0 Cov.: 33 AF XY: 0.00000423 AC XY: 3 AN XY: 709806

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000258

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000170 AC: 2

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

Aug 11, 2021

This sequence change replaces arginine with leucine at codon 7 of the SPAST protein (p.Arg7Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with SPAST-related conditions. 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 not expected to disrupt SPAST protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	27
Dann	Benign	0.97
DEOGEN2	Benign	0.25	T;T;.;.;.;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.67	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.34	T;T;T;T;T;T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	0.69	N;N;N;N;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.6	N;.;N;.;.;.
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;.;D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;.;.
Polyphen		0.65	P;P;.;.;.;.
Vest4		0.64
MutPred		0.33		Loss of methylation at R7 (P = 0.0132);Loss of methylation at R7 (P = 0.0132);Loss of methylation at R7 (P = 0.0132);Loss of methylation at R7 (P = 0.0132);Loss of methylation at R7 (P = 0.0132);Loss of methylation at R7 (P = 0.0132);
MVP		0.77
MPC		0.16
ClinPred		0.47	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.26
gMVP		0.20

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: rs750900931; hg19: chr2-32288920;