2-32154430-C-G

Position:

• chr2-32154430-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1 PM2 PP3_Moderate PP5_Moderate

The NM_014946.4(SPAST):​c.1785C>G​(p.Ser595Arg) variant causes a missense 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. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPAST NM_014946.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.584

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.

• PS1: Transcript NM_014946.4 (SPAST) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848
• PP5: Variant 2-32154430-C-G is Pathogenic according to our data. Variant chr2-32154430-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 857953.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPAST	NM_014946.4	c.1785C>G	p.Ser595Arg	missense_variant	17/17	ENST00000315285.9	NP_055761.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPAST	ENST00000315285.9	c.1785C>G	p.Ser595Arg	missense_variant	17/17	1	NM_014946.4	ENSP00000320885.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 26, 2019

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 missense change has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 24824479, Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with arginine at codon 595 of the SPAST protein (p.Ser595Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D;.;.;.;.;.;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.049
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.97	.;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M;M;.;.;.;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.7	D;.;D;.;.;.;.;.
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;.;D;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;.;.;.;.;.
Polyphen		1.0	D;D;.;.;.;.;.;.
Vest4		0.69
MutPred		0.51		Gain of catalytic residue at S595 (P = 0.015);Gain of catalytic residue at S595 (P = 0.015);.;.;.;.;.;.;
MVP		0.86
MPC		2.3
ClinPred		1.0	D
GERP RS		-3.3
Varity_R		0.99
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs145206063; hg19: chr2-32379499;