2-32141890-ATTT-AT

Variant names:

• chr2-32141890-ATT-A
• rs760322678
• NM_014946.4:c.1494-4_1494-3delTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_014946.4(SPAST):​c.1494-4_1494-3delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000996 in 1,103,962 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPAST NM_014946.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.373
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 147494 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000542 AC: 5 AN: 92222 AF XY: 0.0000412

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000904

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000149

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000456

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000996 AC: 11 AN: 1103962 Hom.: 0 AF XY: 0.00000910 AC XY: 5 AN XY: 549364

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25056

American (AMR) AF: 0.00 AC: 0 AN: 33632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19452

East Asian (EAS) AF: 0.00 AC: 0 AN: 29032

South Asian (SAS) AF: 0.0000313 AC: 2 AN: 63804

European-Finnish (FIN) AF: 0.0000250 AC: 1 AN: 40030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4392

European-Non Finnish (NFE) AF: 0.00000949 AC: 8 AN: 843428

Other (OTH) AF: 0.00 AC: 0 AN: 45136

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 147494 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 71728

African (AFR) AF: 0.00 AC: 0 AN: 40352

American (AMR) AF: 0.00 AC: 0 AN: 14748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.00 AC: 0 AN: 5082

South Asian (SAS) AF: 0.00 AC: 0 AN: 4724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66444

Other (OTH) AF: 0.00 AC: 0 AN: 2020

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs760322678; hg19: chr2-32366959; COSMIC: COSV59516784;