rs1380704736

Variant names:

• chr2-32063742-C-A
• rs1380704736
• NM_014946.4:c.-90C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-32063742-C-A
• chr2-32063742-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_014946.4(SPAST):​c.-90C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,341,076 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: SPAST NM_014946.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.66
• 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: Orphanet, Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).

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.-90C>A		5_prime_UTR	Exon 1 of 17	NP_055761.2
	SPAST	NM_001363823.2		c.-90C>A		5_prime_UTR	Exon 1 of 17	NP_001350752.1	A0A2U3TZR0
	SPAST	NM_199436.2		c.-90C>A		5_prime_UTR	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.-90C>A		5_prime_UTR	Exon 1 of 17	ENSP00000320885.3	Q9UBP0-1
	SPAST	ENST00000713716.1		c.-90C>A		5_prime_UTR	Exon 1 of 18	ENSP00000519019.1	A0AAQ5BGQ0
	SPAST	ENST00000933132.1		c.-90C>A		5_prime_UTR	Exon 1 of 17	ENSP00000603191.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000186 AC: 25 AN: 1341076 Hom.: 0 Cov.: 29 AF XY: 0.0000242 AC XY: 16 AN XY: 659934

African (AFR) AF: 0.00 AC: 0 AN: 30408

American (AMR) AF: 0.00 AC: 0 AN: 34172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22992

East Asian (EAS) AF: 0.00 AC: 0 AN: 35164

South Asian (SAS) AF: 0.00 AC: 0 AN: 73310

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3938

European-Non Finnish (NFE) AF: 0.0000238 AC: 25 AN: 1052482

Other (OTH) AF: 0.00 AC: 0 AN: 56186

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	14
DANN	Benign	0.72
PhyloP100		1.7
PromoterAI		0.0041	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

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: rs1380704736; hg19: chr2-32288811;