2-32087560-G-C

Variant names:

• chr2-32087560-G-C
• rs141944844
• NM_014946.4:c.484G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_014946.4(SPAST):​c.484G>C​(p.Val162Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,444,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V162I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SPAST NM_014946.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.09
• Publications: 1 publications found

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: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, Genomics England PanelApp, Ambry Genetics
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, Charlevoix-Saguenay spastic ataxia, neurodevelopmental disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27448776).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPAST	NM_014946.4	c.484G>C	p.Val162Leu	missense_variant	Exon 2 of 17	ENST00000315285.9	NP_055761.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPAST	ENST00000315285.9	c.484G>C	p.Val162Leu	missense_variant	Exon 2 of 17	1	NM_014946.4	ENSP00000320885.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1444032 Hom.: 0 Cov.: 25 AF XY: 0.00000139 AC XY: 1 AN XY: 719506

African (AFR) AF: 0.00 AC: 0 AN: 33128

American (AMR) AF: 0.00 AC: 0 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25914

East Asian (EAS) AF: 0.00 AC: 0 AN: 39384

South Asian (SAS) AF: 0.00 AC: 0 AN: 85648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1096938

Other (OTH) AF: 0.00 AC: 0 AN: 59708

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;.;.;.;.;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	.;D;D;.;D;D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.2	M;M;M;M;.;.;.;.
PhyloP100		5.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.7	N;.;N;.;.;.;.;.
REVEL	Benign	0.21
Sift	Benign	0.034	D;.;T;.;.;.;.;.
Sift4G	Benign	0.15	T;T;T;.;.;.;.;.
Polyphen		0.93	P;P;.;.;.;.;.;.
Vest4		0.74
MutPred		0.52		Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);.;.;.;.;
MVP		0.45
MPC		0.39
ClinPred		0.91	D
GERP RS		5.5
PromoterAI		-0.034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.37
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs141944844; hg19: chr2-32312629;