chr2-32141890-A-AT

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PVS1_Moderate BP6_Moderate BS1

The NM_014946.4(SPAST):​c.1494-3dupT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00884 in 1,188,068 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 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.010 (0 hom.)
• Consequence: SPAST NM_014946.4 splice_acceptor, 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 -4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.023230687 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.1, offset of 0 (no position change), new splice context is: gctggattttttttttttAGgcg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 2-32141890-A-AT is Benign according to our data. Variant chr2-32141890-A-AT is described in ClinVar as Benign. ClinVar VariationId is 415378.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00023 (34/147548) while in subpopulation SAS AF = 0.000424 (2/4720). AF 95% confidence interval is 0.000139. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPAST	NM_014946.4	MANE Select	c.1494-3dupT		splice_acceptor intron	N/A	NP_055761.2
	SPAST	NM_001363823.2		c.1491-3dupT		splice_acceptor intron	N/A	NP_001350752.1
	SPAST	NM_199436.2		c.1398-3dupT		splice_acceptor intron	N/A	NP_955468.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPAST	ENST00000315285.9	TSL:1 MANE Select	c.1494-14_1494-13insT		intron	N/A	ENSP00000320885.3
	SPAST	ENST00000621856.2	TSL:1	c.1491-14_1491-13insT		intron	N/A	ENSP00000482496.2
	SPAST	ENST00000713716.1		c.1599-14_1599-13insT		intron	N/A	ENSP00000519019.1

Frequencies

GnomAD3 genomes AF: 0.000231 AC: 34 AN: 147472 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000136

Gnomad ASJ AF: 0.000292

Gnomad EAS AF: 0.000394

Gnomad SAS AF: 0.000423

Gnomad FIN AF: 0.000528

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000226

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00951 AC: 877 AN: 92222 AF XY: 0.00958

Gnomad AFR exome AF: 0.00666

Gnomad AMR exome AF: 0.0171

Gnomad ASJ exome AF: 0.00837

Gnomad EAS exome AF: 0.0111

Gnomad FIN exome AF: 0.00682

Gnomad NFE exome AF: 0.00813

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.0101 AC: 10473 AN: 1040520 Hom.: 0 Cov.: 24 AF XY: 0.00973 AC XY: 5033 AN XY: 517398

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

African (AFR) AF: 0.00885 AC: 208 AN: 23512

American (AMR) AF: 0.00759 AC: 241 AN: 31732

Ashkenazi Jewish (ASJ) AF: 0.00717 AC: 131 AN: 18260

East Asian (EAS) AF: 0.00482 AC: 131 AN: 27160

South Asian (SAS) AF: 0.00948 AC: 563 AN: 59418

European-Finnish (FIN) AF: 0.00496 AC: 188 AN: 37940

Middle Eastern (MID) AF: 0.00663 AC: 28 AN: 4222

European-Non Finnish (NFE) AF: 0.0108 AC: 8602 AN: 795754

Other (OTH) AF: 0.00896 AC: 381 AN: 42522

⚠️ 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 AF: 0.000230 AC: 34 AN: 147548 Hom.: 0 Cov.: 32 AF XY: 0.000292 AC XY: 21 AN XY: 71808

African (AFR) AF: 0.000148 AC: 6 AN: 40444

American (AMR) AF: 0.000135 AC: 2 AN: 14762

Ashkenazi Jewish (ASJ) AF: 0.000292 AC: 1 AN: 3422

East Asian (EAS) AF: 0.000394 AC: 2 AN: 5070

South Asian (SAS) AF: 0.000424 AC: 2 AN: 4720

European-Finnish (FIN) AF: 0.000528 AC: 5 AN: 9466

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.000226 AC: 15 AN: 66430

Other (OTH) AF: 0.00 AC: 0 AN: 2038

Alfa AF: 0.0160 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 4 Benign:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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: COSV59514696;