2-32063841-C-G

Variant names:

• chr2-32063841-C-G
• rs937319046
• NM_014946.4:c.10C>G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_014946.4(SPAST):​c.10C>G​(p.Pro4Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000842 in 1,424,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: SPAST NM_014946.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.43

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.34673357).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPAST	NM_014946.4	c.10C>G	p.Pro4Ala	missense_variant	Exon 1 of 17	ENST00000315285.9	NP_055761.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPAST	ENST00000315285.9	c.10C>G	p.Pro4Ala	missense_variant	Exon 1 of 17	1	NM_014946.4	ENSP00000320885.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000103 AC: 2 AN: 194184 Hom.: 0 AF XY: 0.00000935 AC XY: 1 AN XY: 107002

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000361

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000842 AC: 12 AN: 1424454 Hom.: 0 Cov.: 33 AF XY: 0.00000990 AC XY: 7 AN XY: 707056

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000239

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000817

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia Uncertain:1

May 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.25	T;T;.;.;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.043
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.78	.;T;T;.;T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.35	T;T;T;T;T;T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	0.69	N;N;N;N;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.0	N;.;N;.;.;.
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D;.;D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;.;.
Polyphen		0.39	B;B;.;.;.;.
Vest4		0.48
MutPred		0.22		Loss of methylation at K9 (P = 0.0794);Loss of methylation at K9 (P = 0.0794);Loss of methylation at K9 (P = 0.0794);Loss of methylation at K9 (P = 0.0794);Loss of methylation at K9 (P = 0.0794);Loss of methylation at K9 (P = 0.0794);
MVP		0.69
MPC		0.12
ClinPred		0.43	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.29
gMVP		0.089

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

Other links and lift over

dbSNP: rs937319046; hg19: chr2-32288910;