rs144594804

Positions:

chr2-32154380-A-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS2

The ENST00000315285.9(SPAST):c.1735A>C(p.Asn579His) variant causes a missense change. The variant allele was found at a frequency of 0.00064 in 1,613,136 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 1 hom. )

Consequence

SPAST
ENST00000315285.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2O:2

Conservation

PhyloP100: 6.57

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000315285.9

BP4

Computational evidence support a benign effect (MetaRNN=0.17979962).

BP6

Variant 2-32154380-A-C is Benign according to our data. Variant chr2-32154380-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212290.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, Uncertain_significance=7, not_provided=2}. Variant chr2-32154380-A-C is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 48 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPAST	NM_014946.4 linkuse as main transcript	c.1735A>C	p.Asn579His	missense_variant	17/17	ENST00000315285.9	NP_055761.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPAST	ENST00000315285.9 linkuse as main transcript	c.1735A>C	p.Asn579His	missense_variant	17/17	1	NM_014946.4	ENSP00000320885	P4	Q9UBP0-1

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000383

AC:

AN:

250738

Hom.:

AF XY:

0.000428

AC XY:

AN XY:

135598

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.000715

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000674

AC:

984

AN:

1460790

Hom.:

Cov.:

AF XY:

0.000621

AC XY:

451

AN XY:

726784

show subpopulations

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:

0.000431

Gnomad4 NFE exome

AF:

0.000850

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000315

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000611

Hom.:

Bravo

AF:

0.000291

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000461

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:2Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2023	Reported in an individual with an apparently sporadic, adult-onset upper motor neuron syndrome (PMID: 16240363); Reported in two individuals with hereditary spastic paraplegia who harbored a second SPAST variant; however, phase is unknown as parental testing was not performed (PMID: 16055926, 28572275); 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: 20562464, 17594340, 30476002, 24451228, 28572275, 16055926, 34426522, 34445196, 21139634, 26094131, 16240363, 34983064, 27535533) -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as not providedand reported on 04/10/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Hereditary spastic paraplegia 4

Benign:2Other:1

not provided, flagged submission	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 27, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 03, 2023	Variant summary: SPAST c.1735A>C (p.Asn579His) results in a conservative amino acid change located in the Spastin/Vps4, C-terminal (IPR015415) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 250738 control chromosomes, predominantly at a frequency of 0.00072 within the Non-Finnish European subpopulation in the gnomAD database. c.1735A>C has been reported in the literature in individuals affected with Spastic Paraplegia or hereditary ataxia without strong evidence of causality (Brugman_2005, Depienne_2006, Chelban_2017, Parodi_2018, Gelatolo_2021). These reports do not provide unequivocal conclusions about association of the variant with Spastic Paraplegia 4, Autosomal Dominant. Co-occurrence with another pathogenic/likely pathogenic variant has been reported (SPAST c.1216A>G, p.Ile406Val, Depienne_2006), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16240363, 16055926, 28572275, 30476002, 34445196). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=4), benign (n=1) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Paris Brain Institute, Inserm - ICM

- -

Hereditary spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 28, 2019

- -

Spastic ataxia

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris

Jan 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.81

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

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

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

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.18

T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.83

MutationAssessor

Benign

0.94

L;L;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.8

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

REVEL

Pathogenic

0.67

Sift

Benign

0.048

D;.;T;.;.;.;.;.

Sift4G

Benign

0.14

T;T;T;.;.;.;.;.

Polyphen

0.29

B;B;.;.;.;.;.;.

Vest4

0.59

MVP

0.86

MPC

2.2

ClinPred

0.082

GERP RS

5.6

Varity_R

0.71

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

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

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