rs145264166

chr2-32115710-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014946.4(SPAST):c.879G>A(p.Pro293=) 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:11
• Conservation: PhyloP100: 0.991

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 219840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32115710-G-A is described in Lovd as [Benign]. Variant chr2-32115710-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1386 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPAST	NM_014946.4	c.879G>A	p.Pro293=	synonymous_variant	6/17	ENST00000315285.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPAST	ENST00000315285.9	c.879G>A	p.Pro293=	synonymous_variant	6/17	1	NM_014946.4	P4

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

GnomAD3 exomes AF: 0.00943 AC: 2361 AN: 250324 Hom.: 12 AF XY: 0.00964 AC XY: 1306 AN XY: 135428

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 SAS exome AF: 0.00234

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

Gnomad4 AFR exome AF: 0.00207

Gnomad4 AMR exome AF: 0.00670

Gnomad4 ASJ exome AF: 0.0192

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00253

Gnomad4 FIN exome AF: 0.00985

Gnomad4 NFE exome AF: 0.0147

Gnomad4 OTH exome AF: 0.0123

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

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.0106

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.000775

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0105

Gnomad4 NFE AF: 0.0135

Gnomad4 OTH AF: 0.00995

Alfa AF: 0.0126 Hom.: 7

Bravo AF: 0.00911

Asia WGS AF: 0.000579 AC: 2 AN: 3466

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 10, 2020	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Not present in FAST (due to DM? classification). ExAC: 1.4% (898/66366) European. Silent and not in splice consensus. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SPAST: BP4, BP7, BS1, BS2 -

Hereditary spastic paraplegia 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 08, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	12
Dann	Benign	0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs145264166; hg19: chr2-32340779; COSMIC: COSV100188402; COSMIC: COSV100188402;