Genetic Variant SPAST:c.683-9C>T (chr2-32114629-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014946.4(SPAST):c.683-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,612,488 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 26 hom. )

Consequence

SPAST
NM_014946.4 intron

Scores

Splicing: ADA: 0.00003996

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.29

Publications

1 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 2-32114629-C-T is Benign according to our data. Variant chr2-32114629-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0011 (167/152182) while in subpopulation SAS AF = 0.0172 (83/4822). AF 95% confidence interval is 0.0142. There are 2 homozygotes in GnomAd4. There are 103 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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	Effect	Exon Rank	Protein	UniProt
SPAST	NM_014946.4	MANE Select	c.683-9C>T	intron	N/A	NP_055761.2
SPAST	NM_001363823.2		c.680-9C>T	intron	N/A	NP_001350752.1	A0A2U3TZR0
SPAST	NM_199436.2		c.587-9C>T	intron	N/A	NP_955468.1	E5KRP6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SPAST	ENST00000315285.9	TSL:1 MANE Select	c.683-9C>T	intron	N/A	ENSP00000320885.3	Q9UBP0-1
SPAST	ENST00000621856.2	TSL:1	c.680-9C>T	intron	N/A	ENSP00000482496.2	A0A2U3TZR0
SPAST	ENST00000713716.1		c.788-9C>T	intron	N/A	ENSP00000519019.1	A0AAQ5BGQ0

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

168

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00835

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0172

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00238

AC:

597

AN:

250864

AF XY:

0.00319

show subpopulations

Gnomad AFR exome

AF:

0.0000628

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00616

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000537

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.00135

AC:

1968

AN:

1460306

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

1318

AN XY:

726592

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33444

American (AMR)

AF:

0.000313

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00528

AC:

138

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.0153

AC:

1323

AN:

86208

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00972

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000285

AC:

316

AN:

1110650

Other (OTH)

AF:

0.00191

AC:

115

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

187

281

374

468

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00110

AC:

167

AN:

152182

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41534

American (AMR)

AF:

0.00157

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00835

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.0172

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000368

AC:

AN:

67982

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

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:

0.000785

Hom.:

Bravo

AF:

0.000672

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.000948

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 4 (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

3.2

(source)

DANN

Benign

0.74

PhyloP100

-1.3

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000040

dbscSNV1_RF

Benign

0.16

SpliceAI score (max)

0.030

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