rs1555454508

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_025137.4(SPG11):​c.2912_2914delTACinsGAT​(p.IleGln971*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

SPG11
NM_025137.4 stop_gained

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.35
Variant links:
Genes affected
SPG11 (HGNC:11226): (SPG11 vesicle trafficking associated, spatacsin) The protein encoded by this gene is a potential transmembrane protein that is phosphorylated upon DNA damage. Defects in this gene are a cause of spastic paraplegia type 11 (SPG11). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-44615487-GTA-ATC is Pathogenic according to our data. Variant chr15-44615487-GTA-ATC is described in ClinVar as [Pathogenic]. Clinvar id is 522810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SPG11NM_025137.4 linkuse as main transcriptc.2912_2914delTACinsGAT p.IleGln971* stop_gained ENST00000261866.12 NP_079413.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SPG11ENST00000261866.12 linkuse as main transcriptc.2912_2914delTACinsGAT p.IleGln971* stop_gained 1 NM_025137.4 ENSP00000261866.7 Q96JI7-1

Frequencies

GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxDec 06, 2022Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -
Hereditary spastic paraplegia 11 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingUndiagnosed Diseases Network, NIHNov 22, 2016This variant represents a complex allele consisting of a missense change at p.I971 and a stop gain change at p.Q972 acting in cis. It was found [likely] in trans with a pathogenic variant (p.F214fs) in a 23-year-old female with intellectual disability and a progressive motor and cognitive decline. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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.

Other links and lift over

dbSNP: rs1555454508; hg19: chr15-44907685; API