16-89508418-A-G
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePS1_ModeratePM2PP5_Very_Strong
The NM_003119.4(SPG7):āc.1A>Gā(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 0.00000538 in 1,487,502 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 Likely pathogenic (ā ā ).
Frequency
Consequence
NM_003119.4 start_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151888Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000449 AC: 6AN: 1335614Hom.: 0 Cov.: 31 AF XY: 0.00000304 AC XY: 2AN XY: 658600
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151888Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74218
ClinVar
Submissions by phenotype
not provided Pathogenic:3
SPG7: PVS1, PM2 -
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Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 35303589, 23065789) -
Hereditary spastic paraplegia 7 Pathogenic:2
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Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 193253). 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. -
SPG7-related disorder Pathogenic:1
The SPG7 c.1A>G variant is predicted to disrupt the translation initiation site (Start loss). This variant has been reported in individuals with hereditary spastic paraplegia (HSP); in at least one patient, the variant was found along with a second SPG7 frameshift variant (Klebe et al. 2012. PubMed ID: 23065789; Panwala et al. 2022. PubMed ID: 35303589). Other variants that disrupt the start codon have also been reported in HSP patients, in the homozygous state or along with a second heterozygous SPG7 variant (c.1A>T in Elleuch et al. 2006. PubMed ID: 16534102; c.1A>T in Klebe et al. 2012. PubMed ID: 23065789; c.3G>A in van Gassen et al. 2012. PubMed ID: 22964162). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at