2-32141890-ATTT-ATT

Variant names:

• chr2-32141890-AT-A
• rs760322678
• NM_014946.4:c.1494-3delT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_014946.4(SPAST):​c.1494-3delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0391 in 883,178 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.039 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPAST NM_014946.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.175

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 Benign. Variant got -10 ACMG points.

• BP6: Variant 2-32141890-AT-A is Benign according to our data. Variant chr2-32141890-AT-A is described in ClinVar as [Benign]. Clinvar id is 2140310.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-32141890-AT-A is described in Lovd as [Benign]. Variant chr2-32141890-AT-A is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0593 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPAST	NM_014946.4	c.1494-3delT		splice_region_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
SPAST	ENST00000315285.9	c.1494-13delT		intron_variant	Intron 12 of 16	1	NM_014946.4	ENSP00000320885.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 39 AN: 147248 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.000149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000136

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00149

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000241

Gnomad OTH AF: 0.000496

GnomAD4 exome AF: 0.0391 AC: 34542 AN: 883178 Hom.: 0 Cov.: 24 AF XY: 0.0389 AC XY: 16899 AN XY: 434426

Gnomad4 AFR exome AF: 0.0423

Gnomad4 AMR exome AF: 0.0618

Gnomad4 ASJ exome AF: 0.0453

Gnomad4 EAS exome AF: 0.0346

Gnomad4 SAS exome AF: 0.0498

Gnomad4 FIN exome AF: 0.0416

Gnomad4 NFE exome AF: 0.0374

Gnomad4 OTH exome AF: 0.0403

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000272 AC: 40 AN: 147328 Hom.: 0 Cov.: 32 AF XY: 0.000307 AC XY: 22 AN XY: 71680

Gnomad4 AFR AF: 0.000173

Gnomad4 AMR AF: 0.000136

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00149

Gnomad4 NFE AF: 0.000241

Gnomad4 OTH AF: 0.000491

Alfa AF: 0.0812 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 4 Benign:1

Oct 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs760322678; hg19: chr2-32366959;