NM_014946.4:c.1493+18G>A

Variant names:

• chr2-32137206-G-A
• rs189961829
• NM_014946.4:c.1493+18G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014946.4(SPAST):​c.1493+18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000729 in 1,372,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: SPAST NM_014946.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0260
• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPAST	NM_014946.4	c.1493+18G>A		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.1493+18G>A		intron_variant	Intron 12 of 16	1	NM_014946.4	ENSP00000320885.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.29e-7 AC: 1 AN: 1372670 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 688246

African (AFR) AF: 0.00 AC: 0 AN: 31704

American (AMR) AF: 0.00 AC: 0 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25590

East Asian (EAS) AF: 0.00 AC: 0 AN: 39266

South Asian (SAS) AF: 0.00 AC: 0 AN: 84466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5576

European-Non Finnish (NFE) AF: 9.70e-7 AC: 1 AN: 1030682

Other (OTH) AF: 0.00 AC: 0 AN: 57388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.7
DANN	Benign	0.27
PhyloP100		-0.026

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: rs189961829; hg19: chr2-32362275;