chr2-32137137-T-TA

Variant names:

• chr2-32137137-T-TA
• rs1553318313
• NM_014946.4:c.1442_1443insA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_014946.4(SPAST):​c.1442_1443insA​(p.Val482CysfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPAST NM_014946.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.679
• Publications: 3 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 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
• PP5: Variant 2-32137137-T-TA is Pathogenic according to our data. Variant chr2-32137137-T-TA is described in ClinVar as Pathogenic. ClinVar VariationId is 468564.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014946.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPAST	NM_014946.4	MANE Select	c.1442_1443insA	p.Val482CysfsTer6	frameshift	Exon 12 of 17	NP_055761.2
	SPAST	NM_001363823.2		c.1439_1440insA	p.Val481CysfsTer6	frameshift	Exon 12 of 17	NP_001350752.1
	SPAST	NM_199436.2		c.1346_1347insA	p.Val450CysfsTer6	frameshift	Exon 11 of 16	NP_955468.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPAST	ENST00000315285.9	TSL:1 MANE Select	c.1442_1443insA	p.Val482CysfsTer6	frameshift	Exon 12 of 17	ENSP00000320885.3
	SPAST	ENST00000621856.2	TSL:1	c.1439_1440insA	p.Val481CysfsTer6	frameshift	Exon 12 of 17	ENSP00000482496.2
	SPAST	ENST00000713716.1		c.1547_1548insA	p.Val517CysfsTer6	frameshift	Exon 13 of 18	ENSP00000519019.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 4 Pathogenic:1

Mar 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 468564). This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 16832076, 23238845). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val482Cysfs*6) in the SPAST gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPAST are known to be pathogenic (PMID: 20932283).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.68
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1553318313; hg19: chr2-32362206;