2-32141890-ATTT-ATT

Variant names:

• chr2-32141890-AT-A
• rs760322678
• NM_014946.4:c.1494-3delT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_014946.4(SPAST):​c.1494-3delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0391 in 883,178 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.039 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPAST NM_014946.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.175
• 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, Labcorp Genetics (formerly Invitae), Illumina, Genomics England PanelApp, Ambry Genetics
• 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 -2 ACMG points.

• BP6: Variant 2-32141890-AT-A is Benign according to our data. Variant chr2-32141890-AT-A is described in ClinVar as Benign. ClinVar VariationId is 2140310.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPAST	NM_014946.4	c.1494-3delT		splice_region_variant, intron_variant	Intron 12 of 16	ENST00000315285.9	NP_055761.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPAST	ENST00000315285.9	c.1494-13delT		intron_variant	Intron 12 of 16	1	NM_014946.4	ENSP00000320885.3

Frequencies

GnomAD3 genomes AF: 0.000265 AC: 39 AN: 147248 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000136

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00149

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000241

Gnomad OTH AF: 0.000496

GnomAD2 exomes AF: 0.0740 AC: 6822 AN: 92222 AF XY: 0.0752

Gnomad AFR exome AF: 0.0523

Gnomad AMR exome AF: 0.113

Gnomad ASJ exome AF: 0.0649

Gnomad EAS exome AF: 0.0713

Gnomad FIN exome AF: 0.0576

Gnomad NFE exome AF: 0.0659

Gnomad OTH exome AF: 0.0801

GnomAD4 exome AF: 0.0391 AC: 34542 AN: 883178 Hom.: 0 Cov.: 24 AF XY: 0.0389 AC XY: 16899 AN XY: 434426

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0423 AC: 833 AN: 19680

American (AMR) AF: 0.0618 AC: 1538 AN: 24868

Ashkenazi Jewish (ASJ) AF: 0.0453 AC: 627 AN: 13856

East Asian (EAS) AF: 0.0346 AC: 709 AN: 20506

South Asian (SAS) AF: 0.0498 AC: 2338 AN: 46912

European-Finnish (FIN) AF: 0.0416 AC: 1253 AN: 30142

Middle Eastern (MID) AF: 0.0293 AC: 107 AN: 3656

European-Non Finnish (NFE) AF: 0.0374 AC: 25725 AN: 688556

Other (OTH) AF: 0.0403 AC: 1412 AN: 35002

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000272 AC: 40 AN: 147328 Hom.: 0 Cov.: 32 AF XY: 0.000307 AC XY: 22 AN XY: 71680

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000173 AC: 7 AN: 40420

American (AMR) AF: 0.000136 AC: 2 AN: 14724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3420

East Asian (EAS) AF: 0.00 AC: 0 AN: 5070

South Asian (SAS) AF: 0.00 AC: 0 AN: 4718

European-Finnish (FIN) AF: 0.00149 AC: 14 AN: 9406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000241 AC: 16 AN: 66338

Other (OTH) AF: 0.000491 AC: 1 AN: 2036

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0812 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 4 Benign:1

Oct 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism

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: rs760322678; hg19: chr2-32366959; COSMIC: COSV59514150;