rs863224923

Positions:

chr2-32145005-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_014946.4(SPAST):c.1685G>A(p.Arg562Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,607,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SPAST
NM_014946.4 missense, splice_region

Scores

Splicing: ADA: 0.9326

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 8.54

Variant links:

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 links:

SPAST (HGNC:):

SPAST links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 2-32145005-G-A is Pathogenic according to our data. Variant chr2-32145005-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32145005-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPAST	NM_014946.4 linkuse as main transcript	c.1685G>A	p.Arg562Gln	missense_variant, splice_region_variant	15/17	ENST00000315285.9	NP_055761.2	Q9UBP0-1E5KRP5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPAST	ENST00000315285.9 linkuse as main transcript	c.1685G>A	p.Arg562Gln	missense_variant, splice_region_variant	15/17	1	NM_014946.4	ENSP00000320885.3		Q9UBP0-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455664

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724312

show subpopulations

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:

9.03e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 4

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Nov 12, 2024	- -
Pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 05, 2022	This variant disrupts the p.Arg562 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15248095; Invitae). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). ClinVar contains an entry for this variant (Variation ID: 217004). This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 11843700, 17971434, 19423133, 25326637, 27334366). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 562 of the SPAST protein (p.Arg562Gln). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PP3_Moderate+PS4_Moderate+PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Jun 24, 2014	- -

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 01, 2024	PP3, PM1, PM2_moderate, PM5, PS4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2019	Different missense changes at this residue (R562G, R562P) has been reported in the published literature (Svenson et al., 2004; de Bot et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 29934652, 24451228, 22552817, 25326637, 11843700, 19423133) -

Hereditary spastic paraplegia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 01, 2020

- -

SPAST-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 15, 2022

The SPAST c.1685G>A variant is predicted to result in the amino acid substitution p.Arg562Gln. This variant (also known as G1810A, R562Q) was reported in multiple individual with autosomal dominant hereditary spastic paraplegia (Table 3, Meijer et al 2002. PubMed ID: 11843700; Supplemental Table e2, Lee et al 2014. PubMed ID: 25326637; Table 1, Orlacchio et al. 2008. PubMed ID: 17971434; Table 1, Svenstrup et al 2009. PubMed ID: 19423133). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

D;D;.;.;.;.;.;.

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

.;D;D;.;D;D;D;D

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

M;M;.;.;.;.;.;.

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.8

D;.;D;.;.;.;.;.

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

D;.;D;.;.;.;.;.

Sift4G

Uncertain

0.028

D;D;D;.;.;.;.;.

Polyphen

0.85

P;P;.;.;.;.;.;.

Vest4

0.95

MutPred

0.97

Gain of methylation at K565 (P = 0.1048);Gain of methylation at K565 (P = 0.1048);.;.;.;.;.;.;

MVP

0.99

MPC

1.2

ClinPred

0.99

GERP RS

5.6

Varity_R

0.83

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.93

dbscSNV1_RF

Pathogenic

0.80

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over