rs145264166

Positions:

chr2-32115710-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.991

Variant links:

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 links:

SPAST (HGNC:):

SPAST links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1387 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPAST	NM_014946.4 linkuse as main transcript	c.879G>A	p.Pro293Pro	synonymous_variant	6/17	ENST00000315285.9	NP_055761.2	Q9UBP0-1E5KRP5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPAST	ENST00000315285.9 linkuse as main transcript	c.879G>A	p.Pro293Pro	synonymous_variant	6/17	1	NM_014946.4	ENSP00000320885.3		Q9UBP0-1

Frequencies

GnomAD3 genomes

AF:

0.00912

AC:

1386

AN:

151978

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00964

AC XY:

1306

AN XY:

135428

show subpopulations

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.:

AF XY:

0.0125

AC XY:

9048

AN XY:

724200

show subpopulations

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.:

Cov.:

AF XY:

0.00892

AC XY:

663

AN XY:

74356

show subpopulations

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.:

Bravo

AF:

0.00911

Asia WGS

AF:

0.000579

AC:

AN:

3466

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 25, 2024	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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. -

not provided

Benign:4

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	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	SPAST: BP4, BP7, BS1, BS2 -

Hereditary spastic paraplegia 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over