2-32141905-C-T

Position:

• chr2-32141905-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_014946.4(SPAST):​c.1495C>T​(p.Arg499Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R499H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPAST NM_014946.4 missense, splice_region
• Scores: Splicing: ADA: 0.9223
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 2.52

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_014946.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-32141906-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 240950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 2-32141905-C-T is Pathogenic according to our data. Variant chr2-32141905-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32141905-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPAST	NM_014946.4	c.1495C>T	p.Arg499Cys	missense_variant, splice_region_variant	13/17	ENST00000315285.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPAST	ENST00000315285.9	c.1495C>T	p.Arg499Cys	missense_variant, splice_region_variant	13/17	1	NM_014946.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1456098 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724372

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 4 Pathogenic:6 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Mar 21, 2022	The SPAST c.1495C>T variant is classified as Pathogenic (PS4_Moderate, PS3, PM2, PM5) -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 19, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg499 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16009769, 16682546, 18701882, 20562464). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SPAST function (PMID: 15716377). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 5660). This variant is also known as 1620C>T. This missense change has been observed in individuals with hereditary spastic paraplegia (HSP) (PMID: 10610178, 11309678, 12161613, 16055926, 17594340, 17957230, 19438933, 20718791, 25658484, 26208798, 27334366). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 499 of the SPAST protein (p.Arg499Cys). -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease for this gene and are associated with spastic paraplegia 4 (MIM#182601). Multiple loss of function variants have been reported, while a dominant negative mechanism has been stipulated for a small number of missense variants (ClinVar; PMID: 30006150). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance, but this is age-dependent and only a small proportion of individuals remain asymptomatic (PMID: 30476002). (I) 0115 - Variants in this gene are known to have variable expressivity, with variable age of onset and disease severity (PMID: 30476002). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and observed in individuals with hereditary spastic paraplegia, with an elevated risk of cognitive impairment (ClinVar, PMID: 29421991). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	Variant interpreted as Pathogenic and reported on 07-18-2019 by Lab or GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2022	Published functional studies demonstrate a damaging effect on microtubule disassembly and ATPase activity (Errico et al., 2002; Evans et al., 2005); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29980238, 31751864, 15716377, 29934652, 30780198, 30476002, 31285604, 28191889, 34950521, Varghaei2021[pdf], 21139634, 26094131, 17957230, 18701882, 11809724, 11309678, 10610178) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2016	- -

Spastic paraparesis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Sep 15, 2015

- -

Hereditary spastic paraplegia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;D;.;.;.;.;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;H;.;.;.;.;.;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.9	D;.;D;.;.;.;.;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;D;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;.;.;.;.
Polyphen		1.0	D;D;.;.;.;.;.;.
Vest4		0.90
MutPred		0.96		Loss of MoRF binding (P = 0.0082);Loss of MoRF binding (P = 0.0082);.;.;.;.;.;.;
MVP		0.99
MPC		2.6
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Pathogenic	0.75
SpliceAI score (max)		0.010		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: rs121908511; hg19: chr2-32366974; COSMIC: COSV59512800;