2-32063962-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014946.4(SPAST):c.131C>T(p.Ser44Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00785 in 1,612,216 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other,risk factor (★★). Synonymous variant affecting the same amino acid position (i.e. S44S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0050 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0081 ( 65 hom. )

Consequence

SPAST
NM_014946.4 missense

Scores

Clinical Significance

Benign/Likely benign; other; risk factor criteria provided, multiple submitters, no conflicts B:14O:4

Conservation

PhyloP100: 5.07

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011200607).

BP6

Variant 2-32063962-C-T is Benign according to our data. Variant chr2-32063962-C-T is described in ClinVar as [Likely_benign, other, risk_factor]. Clinvar id is 5671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32063962-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.005 (761/152272) while in subpopulation NFE AF= 0.00922 (627/67986). AF 95% confidence interval is 0.00863. There are 6 homozygotes in gnomad4. There are 323 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd at 761 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPAST	NM_014946.4 linkuse as main transcript	c.131C>T	p.Ser44Leu	missense_variant	1/17	ENST00000315285.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPAST	ENST00000315285.9 linkuse as main transcript	c.131C>T	p.Ser44Leu	missense_variant	1/17	1	NM_014946.4	P4	Q9UBP0-1

Frequencies

GnomAD3 genomes

AF:

0.00500

AC:

761

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00922

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00456

AC:

1116

AN:

244870

Hom.:

AF XY:

0.00436

AC XY:

582

AN XY:

133370

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.000729

Gnomad ASJ exome

AF:

0.00181

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00188

Gnomad FIN exome

AF:

0.00240

Gnomad NFE exome

AF:

0.00844

Gnomad OTH exome

AF:

0.00367

GnomAD4 exome

AF:

0.00815

AC:

11895

AN:

1459944

Hom.:

Cov.:

AF XY:

0.00792

AC XY:

5750

AN XY:

726180

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.000830

Gnomad4 ASJ exome

AF:

0.00127

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00239

Gnomad4 FIN exome

AF:

0.00347

Gnomad4 NFE exome

AF:

0.00997

Gnomad4 OTH exome

AF:

0.00528

GnomAD4 genome

AF:

0.00500

AC:

761

AN:

152272

Hom.:

Cov.:

AF XY:

0.00434

AC XY:

323

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00140

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00273

Gnomad4 NFE

AF:

0.00922

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00768

Hom.:

Bravo

AF:

0.00463

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.0112

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00884

AC:

ExAC

AF:

0.00471

AC:

571

Asia WGS

AF:

0.00174

AC:

AN:

3470

ClinVar

Significance: Benign/Likely benign; other; risk factor

Submissions summary: Benign:14Other:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 4

Benign:6Other:2

risk factor, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 06, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 13, 2022	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 12, 2020	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SPAST: PP3, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 17, 2017	- -

SPAST-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 01, 2020

- -

Spastic paraplegia 4, modifier of

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jul 11, 2006

- -

Cerebral palsy

Other:1

other, criteria provided, single submitter

research

Neurogenetics Research Program, University of Adelaide

Jun 10, 2021

Modifier of age of onset/severity of SPG4 (PMID: 30476002, PMID: 17916079) in carrier of paternally inherited SPAST deletion. Modifier of age of onset/severity

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.023

BayesDel_noAF

Pathogenic

0.27

Cadd

Uncertain

Dann

Uncertain

0.98

DEOGEN2

Benign

0.40

T;T;.;.;.;.

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.42

FATHMM_MKL

Uncertain

0.80

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.011

T;T;T;T;T;T

MetaSVM

Uncertain

0.14

MutationAssessor

Benign

0.55

N;N;N;N;.;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.8

N;.;N;.;.;.

REVEL

Uncertain

0.53

Sift

Uncertain

0.0020

D;.;D;.;.;.

Sift4G

Uncertain

0.0030

D;D;D;.;.;.

Polyphen

0.0030

B;B;.;.;.;.

Vest4

0.47

MVP

0.98

MPC

0.11

ClinPred

0.16

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.15

gMVP

0.31

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

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