rs121908515

Variant names:

• chr2-32063962-C-A
• rs121908515
• NM_014946.4:c.131C>A
• SPAST p.Ser44*

Your query was ambiguous. Multiple possible variants found:

• chr2-32063962-C-A
• chr2-32063962-C-T

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+12 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 12 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_Moderate

The NM_014946.4(SPAST):c.131C>A (p.Ser44*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPAST NM_014946.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.07
• Publications: 55 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, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Illumina, Ambry Genetics, Genomics England PanelApp
• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: G2P
• SPAST-related motor disorder

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Stop-gained (exon 1 of 17) at amino acid 44 of 616, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene.
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	PP5Reputable source reports pathogenic		ClinVar 1-star pathogenic — moderate (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 1 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_014946.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SPAST NM_014946.4	MANE Select	c.131C>A p.Ser44*	stop_gained	Exon 1 of 17	Prot: NP_055761.2
	SPAST NM_001363823.2		c.131C>A p.Ser44*	stop_gained	Exon 1 of 17	Prot: NP_001350752.1 UniProt:
	SPAST NM_199436.2		c.131C>A p.Ser44*	stop_gained	Exon 1 of 16	Prot: NP_955468.1 UniProt:

SPAST NM_014946.4

MANE Select

HGVSc / HGVSpc.131C>Ap.Ser44*

Exon rankExon 1 of 17

stop_gained

Prot: NP_055761.2

SPAST NM_001363823.2

HGVSc / HGVSpc.131C>Ap.Ser44*

Exon rankExon 1 of 17

stop_gained

Prot: NP_001350752.1UniProt: A0A2U3TZR0

SPAST NM_199436.2

HGVSc / HGVSpc.131C>Ap.Ser44*

Exon rankExon 1 of 16

stop_gained

Prot: NP_955468.1UniProt: E5KRP6Q9UBP0-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SPAST ENST00000315285.9	TSL:1MANE Select	c.131C>A p.Ser44*	stop_gained	Exon 1 of 17	Prot: ENSP00000320885.3 UniProt:
	SPAST ENST00000621856.2	TSL:1	c.131C>A p.Ser44*	stop_gained	Exon 1 of 17	Prot: ENSP00000482496.2 UniProt:
	SPAST ENST00000713716.1		c.131C>A p.Ser44*	stop_gained	Exon 1 of 18	Prot: ENSP00000519019.1 UniProt:

SPAST ENST00000315285.9

TSL:1MANE Select

HGVSc / HGVSpc.131C>Ap.Ser44*

Exon rankExon 1 of 17

stop_gained

Prot: ENSP00000320885.3UniProt: Q9UBP0-1

SPAST ENST00000621856.2

TSL:1

HGVSc / HGVSpc.131C>Ap.Ser44*

Exon rankExon 1 of 17

stop_gained

Prot: ENSP00000482496.2UniProt: A0A2U3TZR0

SPAST ENST00000713716.1

HGVSc / HGVSpc.131C>Ap.Ser44*

Exon rankExon 1 of 18

stop_gained

Prot: ENSP00000519019.1UniProt: A0AAQ5BGQ0

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000408	AC:1	Hom:	AN:244870	Cov:
GnomAD4 exome Warning	AF: 0.00	AC:0	Hom:0	AN:1459958	Cov:35
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary spastic paraplegia 4 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	37
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	38
DANN	Benign	0.97
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.83	D
GPN-Star LLR	N/A	-5.1
GPN-Star score	N/A	5.1
Mutation Taster	N/A	0/200	disease causing (fs/PTC)
PhyloP100	Uncertain	5.1
PromoterAI	N/A	-0.11	Neutral
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1

Showing 15 of 15 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.070
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs121908515;

hg19: chr2-32289031;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar