Variant chr2-32064120-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014946.4(SPAST):c.289C>T(p.Pro97Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,440,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P97T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SPAST
NM_014946.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.636

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24730077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPAST	NM_014946.4 linkuse as main transcript	c.289C>T	p.Pro97Ser	missense_variant	1/17	ENST00000315285.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPAST	ENST00000315285.9 linkuse as main transcript	c.289C>T	p.Pro97Ser	missense_variant	1/17	1	NM_014946.4	P4	Q9UBP0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000495

AC:

AN:

201842

Hom.:

AF XY:

0.00

AC XY:

AN XY:

110174

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000116

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000208

AC:

AN:

1440728

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714794

show subpopulations

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:

0.00000272

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Uncertain

0.079

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.13

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

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.79

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

M_CAP

Pathogenic

0.93

MetaRNN

Benign

0.25

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

MetaSVM

Benign

-0.38

MutationAssessor

Benign

0.55

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

MutationTaster

Benign

0.67

N;N

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

0.10

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

REVEL

Benign

0.20

Sift

Benign

0.44

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

Sift4G

Benign

0.56

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

Polyphen

0.0020

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

Vest4

0.35

MutPred

0.19

Gain of phosphorylation at P97 (P = 0.0099);Gain of phosphorylation at P97 (P = 0.0099);Gain of phosphorylation at P97 (P = 0.0099);Gain of phosphorylation at P97 (P = 0.0099);Gain of phosphorylation at P97 (P = 0.0099);Gain of phosphorylation at P97 (P = 0.0099);.;.;

MVP

0.52

MPC

0.14

ClinPred

0.11

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.053

gMVP

0.29

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over