NM_014946.4:c.1049C>T

Variant names:

• chr2-32116163-C-T
• rs1060502231
• NM_014946.4:c.1049C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_014946.4(SPAST):​c.1049C>T​(p.Ala350Val) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPAST NM_014946.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.03

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.799
• PP5: Variant 2-32116163-C-T is Pathogenic according to our data. Variant chr2-32116163-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 409035.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPAST	NM_014946.4	c.1049C>T	p.Ala350Val	missense_variant	Exon 7 of 17	ENST00000315285.9	NP_055761.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPAST	ENST00000315285.9	c.1049C>T	p.Ala350Val	missense_variant	Exon 7 of 17	1	NM_014946.4	ENSP00000320885.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 4 Pathogenic:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 350 of the SPAST protein (p.Ala350Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary spastic paraparesis (HSP) (internal data). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this SPAST variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 3,690 individuals referred to our laboratory for SPAST testing. ClinVar contains an entry for this variant (Variation ID: 409035). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SPAST protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

not specified Uncertain:1

Mar 28, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;D;.;.;.;.;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	.;D;D;.;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.3	L;L;.;.;.;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.7	D;.;D;.;.;.;.;.
REVEL	Pathogenic	0.79
Sift	Benign	0.038	D;.;D;.;.;.;.;.
Sift4G	Benign	0.091	T;T;T;.;.;.;.;.
Polyphen		1.0	D;D;.;.;.;.;.;.
Vest4		0.65
MutPred		0.66		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);.;.;.;.;.;.;
MVP		0.85
MPC		2.2
ClinPred		0.98	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.91

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: rs1060502231; hg19: chr2-32341232;