rs750900931

Variant names:

• chr2-32063851-G-A
• rs750900931
• NM_014946.4:c.20G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-32063851-G-A
• chr2-32063851-G-C
• chr2-32063851-G-T

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.20G>A​(p.Arg7Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,429,576 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. R7L) has been classified as Uncertain significance.

• 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: 5.54
• Publications: 0 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: 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

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=0.3068455).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPAST	NM_014946.4	MANE Select	c.20G>A	p.Arg7Gln	missense	Exon 1 of 17	NP_055761.2
	SPAST	NM_001363823.2		c.20G>A	p.Arg7Gln	missense	Exon 1 of 17	NP_001350752.1	A0A2U3TZR0
	SPAST	NM_199436.2		c.20G>A	p.Arg7Gln	missense	Exon 1 of 16	NP_955468.1	E5KRP6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPAST	ENST00000315285.9	TSL:1 MANE Select	c.20G>A	p.Arg7Gln	missense	Exon 1 of 17	ENSP00000320885.3	Q9UBP0-1
	SPAST	ENST00000621856.2	TSL:1	c.20G>A	p.Arg7Gln	missense	Exon 1 of 17	ENSP00000482496.2	A0A2U3TZR0
	SPAST	ENST00000713716.1		c.20G>A	p.Arg7Gln	missense	Exon 1 of 18	ENSP00000519019.1	A0AAQ5BGQ0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1429576 Hom.: 0 Cov.: 33 AF XY: 0.00000141 AC XY: 1 AN XY: 709806

African (AFR) AF: 0.00 AC: 0 AN: 33106

American (AMR) AF: 0.00 AC: 0 AN: 40502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25662

East Asian (EAS) AF: 0.00 AC: 0 AN: 38706

South Asian (SAS) AF: 0.00 AC: 0 AN: 83902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4320

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1102522

Other (OTH) AF: 0.00 AC: 0 AN: 59336

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	0.69	N
PhyloP100		5.5
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.67	N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.052	B
Vest4		0.51
MutPred		0.23		Loss of methylation at R7 (P = 0.0132)
MVP		0.62
MPC		0.15
ClinPred		0.59	D
GERP RS		3.2
PromoterAI		0.065	Neutral
Varity_R		0.24
gMVP		0.18
Mutation Taster		=74/26	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: rs750900931; hg19: chr2-32288920;