rs121908517

Positions:

• chr2-32063965-C-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The ENST00000315285.9(SPAST):​c.134C>A​(p.Pro45Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000832 in 1,612,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P45P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (0 hom.)
• Consequence: SPAST ENST00000315285.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2 O:2
• Conservation: PhyloP100: 1.64

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11625761).
• BP6: Variant 2-32063965-C-A is Benign according to our data. Variant chr2-32063965-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5672.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2, not_provided=1}.
• BS2: High AC in GnomAd4 at 93 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPAST	NM_014946.4	c.134C>A	p.Pro45Gln	missense_variant	1/17	ENST00000315285.9	NP_055761.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPAST	ENST00000315285.9	c.134C>A	p.Pro45Gln	missense_variant	1/17	1	NM_014946.4	ENSP00000320885	P4

Frequencies

GnomAD3 genomes AF: 0.000611 AC: 93 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000912

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000391 AC: 96 AN: 245672 Hom.: 0 AF XY: 0.000396 AC XY: 53 AN XY: 133686

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00136

Gnomad NFE exome AF: 0.000601

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000855 AC: 1249 AN: 1460422 Hom.: 0 Cov.: 35 AF XY: 0.000812 AC XY: 590 AN XY: 726430

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000938

Gnomad4 NFE exome AF: 0.00105

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000611 AC: 93 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.000753 AC XY: 56 AN XY: 74334

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.000912

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000693 Hom.: 0

Bravo AF: 0.000385

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000256 AC: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 4 Uncertain:1 Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2020	Identified in an adult with pure HSP who also harbored a nonsense variant. Authors predict P45Q may act as a phenotype modifier when occurring in the presence of another spastin mutation (McDermott et al., 2006); Reported previously in multiple members of one family (Svenson et al., 2004). Two of the family members were affected with hereditary spastic paraplegia and two of the family members were asymptomatic (Svenson et al., 2004); This variant is associated with the following publications: (PMID: 30834979, 16832076, 20301339, 19730024, 15248095) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2018	- -

Hereditary spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2019

- -

Spastic paraplegia 4, modifier of Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Sep 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.20	T;T;.;.;.;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.64	.;T;T;.;T;T
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.12	T;T;T;T;T;T
MetaSVM	Uncertain	-0.075	T
MutationAssessor	Benign	0.55	N;N;N;N;.;.
MutationTaster	Benign	0.79	A;A
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.35	N;.;N;.;.;.
REVEL	Uncertain	0.30
Sift	Benign	0.046	D;.;D;.;.;.
Sift4G	Benign	0.098	T;T;T;.;.;.
Polyphen		0.067	B;B;.;.;.;.
Vest4		0.27
MVP		0.54
MPC		0.12
ClinPred		0.19	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.066
gMVP		0.23

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: rs121908517; hg19: chr2-32289034;