2-32115710-G-A

Variant names:

• chr2-32115710-G-A
• rs145264166
• NM_014946.4:c.879G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014946.4(SPAST):​c.879G>A​(p.Pro293Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,607,230 control chromosomes in the GnomAD database, including 146 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0091 (8 hom., cov: 33)
  • Exomes 𝑓: 0.013 (138 hom.)
• Consequence: SPAST NM_014946.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.991
• Publications: 8 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 2-32115710-G-A is Benign according to our data. Variant chr2-32115710-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 219840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.991 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00912 (1387/152096) while in subpopulation NFE AF = 0.0135 (920/67998). AF 95% confidence interval is 0.0128. There are 8 homozygotes in GnomAd4. There are 663 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.879G>A	p.Pro293Pro	synonymous	Exon 6 of 17	NP_055761.2
	SPAST	NM_001363823.2		c.876G>A	p.Pro292Pro	synonymous	Exon 6 of 17	NP_001350752.1	A0A2U3TZR0
	SPAST	NM_199436.2		c.783G>A	p.Pro261Pro	synonymous	Exon 5 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.879G>A	p.Pro293Pro	synonymous	Exon 6 of 17	ENSP00000320885.3	Q9UBP0-1
	SPAST	ENST00000621856.2	TSL:1	c.876G>A	p.Pro292Pro	synonymous	Exon 6 of 17	ENSP00000482496.2	A0A2U3TZR0
	SPAST	ENST00000713716.1		c.984G>A	p.Pro328Pro	synonymous	Exon 7 of 18	ENSP00000519019.1	A0AAQ5BGQ0

Frequencies

GnomAD3 genomes AF: 0.00912 AC: 1386 AN: 151978 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.000773

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0105

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.00958

GnomAD2 exomes AF: 0.00943 AC: 2361 AN: 250324 AF XY: 0.00964

Gnomad AFR exome AF: 0.00181

Gnomad AMR exome AF: 0.00624

Gnomad ASJ exome AF: 0.0186

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0107

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.0123

GnomAD4 exome AF: 0.0128 AC: 18683 AN: 1455134 Hom.: 138 Cov.: 29 AF XY: 0.0125 AC XY: 9048 AN XY: 724200

African (AFR) AF: 0.00207 AC: 69 AN: 33370

American (AMR) AF: 0.00670 AC: 299 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.0192 AC: 499 AN: 26024

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39468

South Asian (SAS) AF: 0.00253 AC: 217 AN: 85654

European-Finnish (FIN) AF: 0.00985 AC: 525 AN: 53294

Middle Eastern (MID) AF: 0.00261 AC: 15 AN: 5748

European-Non Finnish (NFE) AF: 0.0147 AC: 16314 AN: 1106804

Other (OTH) AF: 0.0123 AC: 741 AN: 60144

GnomAD4 genome AF: 0.00912 AC: 1387 AN: 152096 Hom.: 8 Cov.: 33 AF XY: 0.00892 AC XY: 663 AN XY: 74356

African (AFR) AF: 0.00214 AC: 89 AN: 41500

American (AMR) AF: 0.0106 AC: 162 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 70 AN: 3470

East Asian (EAS) AF: 0.000775 AC: 4 AN: 5164

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4824

European-Finnish (FIN) AF: 0.0105 AC: 111 AN: 10548

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

European-Non Finnish (NFE) AF: 0.0135 AC: 920 AN: 67998

Other (OTH) AF: 0.00995 AC: 21 AN: 2110

Alfa AF: 0.0126 Hom.: 7

Bravo AF: 0.00911

Asia WGS AF: 0.000579 AC: 2 AN: 3466

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Hereditary spastic paraplegia 4 (2)
-	-	1	Hereditary spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	12
DANN	Benign	0.61
PhyloP100		0.99
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs145264166; hg19: chr2-32340779; COSMIC: COSV100188402; COSMIC: COSV100188402;