rs202209866

Positions:

• chr2-32114629-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014946.4(SPAST):​c.683-9C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,612,488 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (26 hom.)
• Consequence: SPAST NM_014946.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003996
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.29

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 2-32114629-C-T is Benign according to our data. Variant chr2-32114629-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 197814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0011 (167/152182) while in subpopulation SAS AF= 0.0172 (83/4822). AF 95% confidence interval is 0.0142. There are 2 homozygotes in gnomad4. There are 103 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 167 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPAST	NM_014946.4	c.683-9C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000315285.9	NP_055761.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPAST	ENST00000315285.9	c.683-9C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_014946.4	ENSP00000320885	P4

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 168 AN: 152064 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00238 AC: 597 AN: 250864 Hom.: 5 AF XY: 0.00319 AC XY: 433 AN XY: 135798

Gnomad AFR exome AF: 0.0000628

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00616

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0149

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000537

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00135 AC: 1968 AN: 1460306 Hom.: 26 Cov.: 31 AF XY: 0.00181 AC XY: 1318 AN XY: 726592

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00528

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0153

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000285

Gnomad4 OTH exome AF: 0.00191

GnomAD4 genome AF: 0.00110 AC: 167 AN: 152182 Hom.: 2 Cov.: 32 AF XY: 0.00138 AC XY: 103 AN XY: 74402

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00835

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0172

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000785 Hom.: 0

Bravo AF: 0.000672

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000948

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 16, 2015	- -

Hereditary spastic paraplegia 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	3.2
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000040
dbscSNV1_RF	Benign	0.16
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

Publications

LitVar

Other links and lift over

dbSNP: rs202209866; hg19: chr2-32339698;