2-32141890-ATTT-ATTTT

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PVS1_Moderate BP6_Moderate BS1 BS2

The NM_014946.4(SPAST):​c.1494-3dupT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00884 in 1,188,068 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 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.010 (0 hom.)
• Consequence: SPAST NM_014946.4 splice_acceptor, 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 -8 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 7.1, offset of 0 (no position change), new splice context is: gctggattttttttttttAGgcg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 2-32141890-A-AT is Benign according to our data. Variant chr2-32141890-A-AT is described in ClinVar as [Benign]. Clinvar id is 415378.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00023 (34/147548) while in subpopulation SAS AF= 0.000424 (2/4720). AF 95% confidence interval is 0.000139. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPAST	NM_014946.4	c.1494-3dupT		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
SPAST	ENST00000315285.9	c.1494-14_1494-13insT		intron_variant	Intron 12 of 16	1	NM_014946.4	ENSP00000320885.3

Frequencies

GnomAD3 genomes AF: 0.000231 AC: 34 AN: 147472 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000136

Gnomad ASJ AF: 0.000292

Gnomad EAS AF: 0.000394

Gnomad SAS AF: 0.000423

Gnomad FIN AF: 0.000528

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000226

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0101 AC: 10473 AN: 1040520 Hom.: 0 Cov.: 24 AF XY: 0.00973 AC XY: 5033 AN XY: 517398

Gnomad4 AFR exome AF: 0.00885

Gnomad4 AMR exome AF: 0.00759

Gnomad4 ASJ exome AF: 0.00717

Gnomad4 EAS exome AF: 0.00482

Gnomad4 SAS exome AF: 0.00948

Gnomad4 FIN exome AF: 0.00496

Gnomad4 NFE exome AF: 0.0108

Gnomad4 OTH exome AF: 0.00896

GnomAD4 genome AF: 0.000230 AC: 34 AN: 147548 Hom.: 0 Cov.: 32 AF XY: 0.000292 AC XY: 21 AN XY: 71808

Gnomad4 AFR AF: 0.000148

Gnomad4 AMR AF: 0.000135

Gnomad4 ASJ AF: 0.000292

Gnomad4 EAS AF: 0.000394

Gnomad4 SAS AF: 0.000424

Gnomad4 FIN AF: 0.000528

Gnomad4 NFE AF: 0.000226

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 4 Benign:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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;