rs878854991

Positions:

• chr2-32141906-G-A
• chr2-32141906-G-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.1496G>A​(p.Arg499His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. 1/1 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. R499?) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SPAST NM_014946.4 missense, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:26 U:1
• Conservation: PhyloP100: 8.02

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 helix (size 2) in uniprot entity SPAST_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) 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 chr2-32141904-GCG-GT is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 2-32141906-G-A is Pathogenic according to our data. 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. Variant chr2-32141906-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPAST	NM_014946.4	c.1496G>A	p.Arg499His	missense_variant, splice_region_variant	13/17	ENST00000315285.9	NP_055761.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPAST	ENST00000315285.9	c.1496G>A	p.Arg499His	missense_variant, splice_region_variant	13/17	1	NM_014946.4	ENSP00000320885	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455968 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724242

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:26 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 4 Pathogenic:17

Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Oct 14, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 499 of the SPAST protein (p.Arg499His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary spastic paraplegia 4 (PMID: 16009769, 16055926, 16682546, 18701882, 20562464). ClinVar contains an entry for this variant (Variation ID: 240950). 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. 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: 15095758, 15716377). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	National Institute of Neuroscience, National Center of Neurology and Psychiatry	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 26, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 17, 2016	This variant was identified as de novo (maternity and paternity confirmed). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neurogenetics Laboratory, Gh Pitie Salpetriere Aphp	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Aug 12, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Sep 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 29421991, 27260292, 16009769, 16055926, PS4_S). The variant has been previously reported as de novo in a similarly affected individual (PMID: 29421991, PS2_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005660,VCV000801664, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.986, 3CNET: 0.998, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	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 associated with 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 is mostly age-dependant penetrance 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 histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is a recurrent variant in individuals with spastic paraplegia, often occured de novo and has highly variable expressivity (ClinVar, DECIPHER, PMID: 34753439). (SP) 0600 - Variant is located in the annotated AAA domain (DECIPHER). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 31, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Aug 17, 2022	ACMG classification criteria: PS3 supporting, PS4 strong, PM1 moderated, PM2 moderated, PM6 moderated, PP3 supporting -
Pathogenic, no assertion criteria provided	clinical testing	Human Genetics, University of Luebeck	Dec 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Aug 21, 2018	- -

not provided Pathogenic:5 Uncertain:1

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Jan 29, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 12, 2019	PS4, PM1, PM2, PM5, PM6, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27260292, 16009769, 29761117, 29421991, 29980238, 30564185, 31486053, 31157359, 31227335, 30476002, 31216405, 31698101, 31031587, 33098801, 33624935) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 21, 2017	- -

Abnormal central motor function Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2016

- -

SPAST-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 10, 2023

The SPAST c.1496G>A variant is predicted to result in the amino acid substitution p.Arg499His. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It has been reported in multiple patients with autosomal dominant spastic paraplegia (Depienne et al. 2006. PubMed ID: 16055926; Shoukier et al. 2009. PubMed ID: 18701882; de Bot et al. 2010. PubMed ID: 20562464; Kim et al. 2014. PubMed ID: 25045380; Polymeris et al. 2016. PubMed ID: 27260292). A different substitution affecting the same amino acid residue (p.Arg499Cys) has also been reported to be pathogenic for autosomal dominant spastic paraplegia (Depienne et al. 2006. PubMed ID: 16055926, Hazan et al. 1999. PubMed ID: 10610178; Evans et al. 2005. PubMed ID: 15716377; Shoukier et al. 2009. PubMed ID: 18701882). Taken together, we interpret the c.1496G>A (p.Arg499His) variant as pathogenic. -

Hereditary spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;D;.;.;.;.;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;H;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.0	D;.;D;.;.;.;.;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;.;D;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;.;.;.;.
Polyphen		1.0	D;D;.;.;.;.;.;.
Vest4		0.99
MutPred		0.98		Loss of MoRF binding (P = 0.0189);Loss of MoRF binding (P = 0.0189);.;.;.;.;.;.;
MVP		0.98
MPC		2.4
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.96
gMVP		0.98

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: rs878854991; hg19: chr2-32366975;