rs1060499524
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_015087.5(SPART):βc.1110delβ(p.Lys370AsnfsTer30) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000013 ( 0 hom., cov: 33)
Exomes π: 0.0000021 ( 0 hom. )
Consequence
SPART
NM_015087.5 frameshift
NM_015087.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.309
Genes affected
SPART (HGNC:18514): (spartin) This gene encodes a protein containing a MIT (Microtubule Interacting and Trafficking molecule) domain, and is implicated in regulating endosomal trafficking and mitochondria function. The protein localizes to mitochondria and partially co-localizes with microtubules. Stimulation with epidermal growth factor (EGF) results in protein translocation to the plasma membrane, and the protein functions in the degradation and intracellular trafficking of EGF receptor. Multiple alternatively spliced variants, encoding the same protein, have been identified. Mutations associated with this gene cause autosomal recessive spastic paraplegia 20 (Troyer syndrome). [provided by RefSeq, Nov 2008]
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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
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Very rare variant in population databases, with high coverage;
PP5
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Variant 13-36329415-GT-G is Pathogenic according to our data. Variant chr13-36329415-GT-G is described in ClinVar as [Pathogenic]. Clinvar id is 3457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPART | NM_015087.5 | c.1110del | p.Lys370AsnfsTer30 | frameshift_variant | 4/9 | ENST00000438666.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPART | ENST00000438666.7 | c.1110del | p.Lys370AsnfsTer30 | frameshift_variant | 4/9 | 1 | NM_015087.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152142Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251444Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135892
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461828Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727214
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152142Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74316
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Troyer syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2008 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 22, 2023 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 08, 2023 | This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Lys370Asnfs*30) in the SPART gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPART are known to be pathogenic (PMID: 18413476, 20437587, 20504295). This premature translational stop signal has been observed in individuals with Troyer syndrome (PMID: 12134148, 18413476). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3457). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 21, 2018 | The c.1110delA variant in the SPG20 gene has been reported previously in the homozygous state in association with Troyer syndrome (Patel et al., 2002; Bakowska et al., 2008). The c.1110delA variant is considered a founder mutation in the Old Order Amish population (Patel et al., 2002). The c.1110delA pathogenic variant causes a frameshift starting with codon Lysine 370, changes this amino acid to an Asparagine residue and creates a premature Stop codon at position 30 of the new reading frame, denoted p.Lys370AsnfsX30. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Furthermore, the c.1110delA variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.1110delA as a pathogenic variant. - |
SPART-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 17, 2024 | The SPART c.1110delA variant is predicted to result in a frameshift and premature protein termination (p.Lys370Asnfs*30). This variant was reported in the homozygous state in many Old Order Amish with Troyer syndrome (Patel et al 2002. PubMed ID: 12134148; Bakowska JC et al 2008. PubMed ID: 18413476). This variant is reported in 0.0015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in SPART are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at