rs1332265538
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_ModeratePS1_ModeratePM2PP5
The NM_003119.4(SPG7):c.2T>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000403 in 1,488,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_003119.4 start_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151976Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000374 AC: 5AN: 1336898Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 659250
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151976Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74268
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 7 Pathogenic:2
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For these reasons, this variant has been classified as Pathogenic. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 1070427). Disruption of the initiator codon has been observed in individuals with hereditary spastic paraplegia (PMID: 22964162, 23065789; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the SPG7 mRNA. The next in-frame methionine is located at codon 44. -
not specified Uncertain:1
Variant summary: SPG7 c.2T>A (p.Met1Lys) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. An alternative downstream in-frame start codon (Met44) is located in the encoded protein. An activation of this potential downstream translation initiation site would result in a shortened protein missing the first 43 amino acids from the protein sequence. To our knowledge no other pathogenic variants has been reported upstream of this alternate codon. Two of two in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 89584 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2T>A in individuals affected with Hereditary Spastic Paraplegia 7 and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at