GeneBe

2-32141890-ATTT-ATTTTTT

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_014946.4(SPAST):​c.1494-5_1494-3dupTTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000905 in 1,105,416 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 9.0e-7 ( 0 hom. )

Consequence

SPAST
NM_014946.4 splice_acceptor, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.175

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.023230687 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.3, offset of 0 (no position change), new splice context is: tggattttttttttttttAGgcg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPASTNM_014946.4 linkc.1494-5_1494-3dupTTT splice_acceptor_variant, intron_variant Intron 12 of 16 ENST00000315285.9 NP_055761.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPASTENST00000315285.9 linkc.1494-14_1494-13insTTT intron_variant Intron 12 of 16 1 NM_014946.4 ENSP00000320885.3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
9.05e-7
AC:
1
AN:
1105416
Hom.:
0
Cov.:
24
AF XY:
0.00000182
AC XY:
1
AN XY:
550016
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
25084
American (AMR)
AF:
0.00
AC:
0
AN:
33670
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
29048
South Asian (SAS)
AF:
0.0000156
AC:
1
AN:
63910
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
40076
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4398
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
844576
Other (OTH)
AF:
0.00
AC:
0
AN:
45186
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
0.17

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs760322678; hg19: chr2-32366959; API