2-32128478-AC-A

Position:

• chr2-32128478-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PM2 PP3_Moderate PP5_Very_Strong

The NM_014946.4(SPAST):​c.1245del​(p.Tyr415Ter) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y415Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPAST NM_014946.4 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.713

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 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-32128478-AC-A is Pathogenic according to our data. Variant chr2-32128478-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 216109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPAST	NM_014946.4	c.1245del	p.Tyr415Ter	frameshift_variant, splice_region_variant	9/17	ENST00000315285.9	NP_055761.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPAST	ENST00000315285.9	c.1245del	p.Tyr415Ter	frameshift_variant, splice_region_variant	9/17	1	NM_014946.4	ENSP00000320885	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 07, 2023

This variant is expected to result in the loss of a functional protein. This variant has been identified in at least one individual with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). -

Hereditary spastic paraplegia 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2017

For these reasons, this variant has been classified as Pathogenic. Truncating variants in SPAST are known to be pathogenic. This variation has been reported in individuals affected with hereditary spastic paraplegia (PMID: 18701882, 19875132). This sequence change deletes 1 nucleotide in exon 9 of the SPAST mRNA (c.1245delC), causing a frameshift at codon 415. This creates a premature translational stop signal (p.Tyr415*) and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.86		Position offset: 0
DS_DL_spliceai		0.98		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs863224513; hg19: chr2-32353547;