Genetic Variant SPAST:p.Ser44Leu (chr2-32063962-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_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:15O:4

Conservation

PhyloP100: 5.07

Publications

52 publications found

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 Gene-Disease associations (from GenCC):

hereditary spastic paraplegia 4
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Orphanet
Charlevoix-Saguenay spastic ataxia
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
neurodevelopmental disorder
Inheritance: AD Classification: STRONG Submitted by: G2P
SPAST-related motor disorder
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics

SPAST links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 148 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. Gene score misZ: 1.2438 (below the threshold of 3.09). Trascript score misZ: 0.22274 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary spastic paraplegia 4, SPAST-related motor disorder, neurodevelopmental disorder, Charlevoix-Saguenay spastic ataxia.

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 Benign/Likely_benign|other|risk_factor. ClinVar VariationId is 5671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014946.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPAST	NM_014946.4	MANE Select	c.131C>T	p.Ser44Leu	missense	Exon 1 of 17	NP_055761.2
SPAST	NM_001363823.2		c.131C>T	p.Ser44Leu	missense	Exon 1 of 17	NP_001350752.1	A0A2U3TZR0
SPAST	NM_199436.2		c.131C>T	p.Ser44Leu	missense	Exon 1 of 16	NP_955468.1	E5KRP6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPAST	ENST00000315285.9	TSL:1 MANE Select	c.131C>T	p.Ser44Leu	missense	Exon 1 of 17	ENSP00000320885.3	Q9UBP0-1
SPAST	ENST00000621856.2	TSL:1	c.131C>T	p.Ser44Leu	missense	Exon 1 of 17	ENSP00000482496.2	A0A2U3TZR0
SPAST	ENST00000713716.1		c.131C>T	p.Ser44Leu	missense	Exon 1 of 18	ENSP00000519019.1	A0AAQ5BGQ0

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

GnomAD2 exomes

AF:

0.00456

AC:

1116

AN:

244870

AF XY:

0.00436

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 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

African (AFR)

AF:

0.00111

AC:

AN:

33376

American (AMR)

AF:

0.000830

AC:

AN:

44586

Ashkenazi Jewish (ASJ)

AF:

0.00127

AC:

AN:

26062

East Asian (EAS)

AF:

0.00

AC:

AN:

39620

South Asian (SAS)

AF:

0.00239

AC:

206

AN:

86060

European-Finnish (FIN)

AF:

0.00347

AC:

185

AN:

53272

Middle Eastern (MID)

AF:

0.00106

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

0.00997

AC:

11073

AN:

1111036

Other (OTH)

AF:

0.00528

AC:

318

AN:

60264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

639

1278

1916

2555

3194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

444

888

1332

1776

2220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00500

AC:

761

AN:

152272

Hom.:

Cov.:

AF XY:

0.00434

AC XY:

323

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

41564

American (AMR)

AF:

0.00105

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00269

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00273

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00922

AC:

627

AN:

67986

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

130

173

216

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00712

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

ClinVar submissions

Significance:Benign/Likely benign; other; risk factor

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 4 (8)

not provided (4)

not specified (3)

Hereditary spastic paraplegia (1)

SPAST-related disorder (1)

Cerebral palsy (1)

SPASTIC PARAPLEGIA 4, MODIFIER OF (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.023

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.40

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.42

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.87

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.011

MetaSVM

Uncertain

0.14

MutationAssessor

Benign

0.55

PhyloP100

5.1

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.53

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Polyphen

0.0030

Vest4

0.47

MVP

0.98

MPC

0.11

ClinPred

0.16

GERP RS

3.3

PromoterAI

-0.058

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.15

gMVP

0.31

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over