2-32064111-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_014946.4(SPAST):c.280G>C(p.Gly94Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000375 in 1,601,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

SPAST
NM_014946.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.473

Publications

0 publications found

Variant links:

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]

SPAST Gene-Disease associations (from GenCC):

hereditary spastic paraplegia 4
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, Genomics England PanelApp, Ambry Genetics
Charlevoix-Saguenay spastic ataxia
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
neurodevelopmental disorder
Inheritance: AD Classification: STRONG Submitted by: G2P
SPAST-related motor disorder
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics

SPAST links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 148 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. Gene score misZ: 1.2438 (below the threshold of 3.09). Trascript score misZ: 0.22274 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary spastic paraplegia 4, SPAST-related motor disorder, Charlevoix-Saguenay spastic ataxia, neurodevelopmental disorder.

BP4

Computational evidence support a benign effect (MetaRNN=0.19330484).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPAST	NM_014946.4 link	c.280G>C	p.Gly94Arg	missense_variant	Exon 1 of 17	ENST00000315285.9	NP_055761.2	Q9UBP0-1E5KRP5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPAST	ENST00000315285.9 link	c.280G>C	p.Gly94Arg	missense_variant	Exon 1 of 17	1	NM_014946.4	ENSP00000320885.3		Q9UBP0-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000460

AC:

AN:

217472

AF XY:

0.00

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000182

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1449002

Hom.:

Cov.:

AF XY:

0.00000417

AC XY:

AN XY:

719700

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33224

American (AMR)

AF:

0.0000467

AC:

AN:

42808

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25810

East Asian (EAS)

AF:

0.00

AC:

AN:

39260

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84576

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51972

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5226

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106372

Other (OTH)

AF:

0.0000167

AC:

AN:

59754

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152052

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74260

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41446

American (AMR)

AF:

0.0000655

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67966

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 4

Uncertain:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 94 of the SPAST protein (p.Gly94Arg). This variant is present in population databases (no rsID available, gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SPAST-related conditions. ClinVar contains an entry for this variant (Variation ID: 1385194). 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 95%. 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

Benign

0.10

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.14

T;T;.;.;.;.;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.71

.;T;T;.;T;T;T;T

M_CAP

Pathogenic

0.92

MetaRNN

Benign

0.19

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

0.0

N;N;N;N;.;.;.;.

PhyloP100

-0.47

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

0.54

N;.;N;.;.;.;.;.

REVEL

Uncertain

0.33

Sift

Benign

0.60

T;.;T;.;.;.;.;.

Sift4G

Benign

0.23

T;T;T;.;.;.;.;.

Polyphen

0.0

B;B;.;.;.;.;.;.

Vest4

0.13

MutPred

0.22

Gain of MoRF binding (P = 0.013);Gain of MoRF binding (P = 0.013);Gain of MoRF binding (P = 0.013);Gain of MoRF binding (P = 0.013);Gain of MoRF binding (P = 0.013);Gain of MoRF binding (P = 0.013);.;.;

MVP

0.27

MPC

0.15

ClinPred

0.056

GERP RS

-0.88

PromoterAI

0.0031

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.046

gMVP

0.14

Mutation Taster

=80/20

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over