rs568556987
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_003119.4(SPG7):c.1937-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,613,330 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
SPG7
NM_003119.4 splice_acceptor, intron
NM_003119.4 splice_acceptor, intron
Scores
3
3
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 8.96
Genes affected
SPG7 (HGNC:11237): (SPG7 matrix AAA peptidase subunit, paraplegin) This gene encodes a mitochondrial metalloprotease protein that is a member of the AAA 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. Mutations in this gene cause autosomal recessive spastic paraplegia 7. Two transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Mar 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.8, offset of 8, new splice context is: cccgccctccgggggcacAGgac. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-89553792-A-G is Pathogenic according to our data. Variant chr16-89553792-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 465174.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SPG7 | NM_003119.4 | c.1937-2A>G | splice_acceptor_variant, intron_variant | ENST00000645818.2 | NP_003110.1 | |||
SPG7 | NM_001363850.1 | c.1937-2A>G | splice_acceptor_variant, intron_variant | NP_001350779.1 | ||||
SPG7 | XM_047434537.1 | c.1064-2A>G | splice_acceptor_variant, intron_variant | XP_047290493.1 | ||||
SPG7 | XM_047434540.1 | c.623-2A>G | splice_acceptor_variant, intron_variant | XP_047290496.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SPG7 | ENST00000645818.2 | c.1937-2A>G | splice_acceptor_variant, intron_variant | NM_003119.4 | ENSP00000495795.2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152180Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250482Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135692
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GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461032Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 726830
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152298Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74472
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 7 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 03, 2020 | For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SPG7 are known to be pathogenic (PMID: 21623769, 22964162). Disruption of this splice site has been observed in combination with another SPG7 variant in individuals with clinical features of hereditary spastic paraplegia and to segregate with disease in a family (PMID: 22964162, 30533525). ClinVar contains an entry for this variant (Variation ID: 465174). This variant is present in population databases (rs568556987, ExAC 0.02%). This sequence change affects an acceptor splice site in intron 14 of the SPG7 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 05, 2024 | This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with clinical features associated with this gene. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
GERP RS
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 10
DS_AL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at