2-32114825-G-C

Position:

chr2-32114825-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_014946.4(SPAST):c.870G>C(p.Lys290Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,460,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SPAST
NM_014946.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.26

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-32114825-G-C is Pathogenic according to our data. Variant chr2-32114825-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1807003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPAST	NM_014946.4 linkuse as main transcript	c.870G>C	p.Lys290Asn	missense_variant, splice_region_variant	5/17	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.870G>C	p.Lys290Asn	missense_variant, splice_region_variant	5/17	1	NM_014946.4	ENSP00000320885.3		Q9UBP0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251228

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135782

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460668

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726772

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	SPAST: PS1, PM2, PM5, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 16, 2022	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. This variant results in the same amino acid change as another variant considered to be pathogenic or likely pathogenic, strongly indicating this variant may also cause disease. Computational tools yielded predictions that this variant may interfere with normal RNA splicing. -

Hereditary spastic paraplegia 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 03, 2023

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 290 of the SPAST protein (p.Lys290Asn). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 5 and introduces a premature termination codon (PMID: 11309678). The resulting mRNA is expected to undergo nonsense-mediated decay. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 1807003). This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 11309678, 30476002). This variant is present in population databases (no rsID available, gnomAD 0.003%). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.38

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

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

Eigen

Benign

-0.14

Eigen_PC

Benign

0.0098

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

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

M_CAP

Benign

0.023

MetaRNN

Benign

0.18

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

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.3

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

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.29

N;.;N;.;.;.;.;.

REVEL

Benign

0.059

Sift

Benign

0.38

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

Sift4G

Benign

0.42

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

Polyphen

0.038

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

Vest4

0.42

MutPred

0.23

Loss of glycosylation at K290 (P = 0.029);Loss of glycosylation at K290 (P = 0.029);.;.;.;.;.;.;

MVP

0.65

MPC

0.25

ClinPred

0.56

GERP RS

4.6

Varity_R

0.12

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.90

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.90

Position offset: 0

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