rs141944844

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-32087560-G-A
• chr2-32087560-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014946.4(SPAST):​c.484G>A​(p.Val162Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00159 in 1,596,058 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (7 hom.)
• Consequence: SPAST NM_014946.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 5.09
• Publications: 7 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: 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, Charlevoix-Saguenay spastic ataxia, neurodevelopmental disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0048749745).
• BP6: Variant 2-32087560-G-A is Benign according to our data. Variant chr2-32087560-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 335829.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 = 0.00181 (276/152068) while in subpopulation NFE AF = 0.00172 (117/67990). AF 95% confidence interval is 0.00147. There are 3 homozygotes in GnomAd4. There are 152 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPAST	NM_014946.4	MANE Select	c.484G>A	p.Val162Ile	missense	Exon 2 of 17	NP_055761.2
	SPAST	NM_001363823.2		c.481G>A	p.Val161Ile	missense	Exon 2 of 17	NP_001350752.1	A0A2U3TZR0
	SPAST	NM_199436.2		c.484G>A	p.Val162Ile	missense	Exon 2 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.484G>A	p.Val162Ile	missense	Exon 2 of 17	ENSP00000320885.3	Q9UBP0-1
	SPAST	ENST00000621856.2	TSL:1	c.481G>A	p.Val161Ile	missense	Exon 2 of 17	ENSP00000482496.2	A0A2U3TZR0
	SPAST	ENST00000713716.1		c.484G>A	p.Val162Ile	missense	Exon 2 of 18	ENSP00000519019.1	A0AAQ5BGQ0

Frequencies

GnomAD3 genomes AF: 0.00182 AC: 276 AN: 151950 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00172

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00200 AC: 502 AN: 250848 AF XY: 0.00203

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0138

Gnomad NFE exome AF: 0.00156

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00156 AC: 2254 AN: 1443990 Hom.: 7 Cov.: 25 AF XY: 0.00152 AC XY: 1095 AN XY: 719478

African (AFR) AF: 0.000241 AC: 8 AN: 33128

American (AMR) AF: 0.000202 AC: 9 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: 0.0132 AC: 698 AN: 53022

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

European-Non Finnish (NFE) AF: 0.00133 AC: 1457 AN: 1096904

Other (OTH) AF: 0.00137 AC: 82 AN: 59706

GnomAD4 genome AF: 0.00181 AC: 276 AN: 152068 Hom.: 3 Cov.: 32 AF XY: 0.00204 AC XY: 152 AN XY: 74336

African (AFR) AF: 0.000217 AC: 9 AN: 41510

American (AMR) AF: 0.000393 AC: 6 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.0135 AC: 142 AN: 10524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00172 AC: 117 AN: 67990

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00127 Hom.: 1

Bravo AF: 0.000748

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00188 AC: 228

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hereditary spastic paraplegia 4 (4)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	SPAST-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.071
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.61	N
PhyloP100		5.1
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.18
Sift	Benign	0.48	T
Sift4G	Benign	0.48	T
Polyphen		0.17	B
Vest4		0.37
MVP		0.79
MPC		0.14
ClinPred		0.012	T
GERP RS		5.5
PromoterAI		-0.048	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.064
gMVP		0.14
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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;