chr2-32128483-A-G

Variant names:

• chr2-32128483-A-G
• rs587777755
• NM_014946.4:c.1245+4A>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_014946.4(SPAST):​c.1245+4A>G variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPAST NM_014946.4 splice_region, intron
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.31
• Publications: 2 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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-32128483-A-G is Pathogenic according to our data. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32128483-A-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPAST	NM_014946.4	c.1245+4A>G		splice_region_variant, intron_variant	Intron 9 of 16	ENST00000315285.9	NP_055761.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPAST	ENST00000315285.9	c.1245+4A>G		splice_region_variant, intron_variant	Intron 9 of 16	1	NM_014946.4	ENSP00000320885.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 4 Pathogenic:2

Jul 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 9 of the SPAST gene. It does not directly change the encoded amino acid sequence of the SPAST protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with hereditary spastic paraplegia (PMID: 11309678). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS9+4A>G. ClinVar contains an entry for this variant (Variation ID: 5666). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

May 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Apr 25, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported to segregate with HSP in a family in the published literature; however details of the pedigree were not provided (Svenson et al., 2001; McCorquodale et al., 2011); Published functional studies demonstrate that this variant results in leaky splicing and skipping of exon 9 (Svenson et al., 2001); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25525159, 20718791, 11309678) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
CADD	Benign	16
DANN	Benign	0.97
PhyloP100		8.3
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.91		Position offset: -4

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

Other links and lift over

dbSNP: rs587777755; hg19: chr2-32353552;