rs769602042
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_003119.4(SPG7):c.1948G>A(p.Asp650Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,334 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D650Y) has been classified as Likely pathogenic.
Frequency
Consequence
NM_003119.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPG7 | NM_003119.4 | c.1948G>A | p.Asp650Asn | missense_variant | 15/17 | ENST00000645818.2 | |
SPG7 | NM_001363850.1 | c.1948G>A | p.Asp650Asn | missense_variant | 15/18 | ||
SPG7 | XM_047434537.1 | c.1075G>A | p.Asp359Asn | missense_variant | 10/13 | ||
SPG7 | XM_047434540.1 | c.634G>A | p.Asp212Asn | missense_variant | 7/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPG7 | ENST00000645818.2 | c.1948G>A | p.Asp650Asn | missense_variant | 15/17 | NM_003119.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152220Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250772Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135786
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461114Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11AN XY: 726874
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152220Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74360
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 7 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 08, 2023 | Variant summary: SPG7 c.1948G>A (p.Asp650Asn) results in a conservative amino acid change located in the Peptidase M41 domain (IPR000642) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250772 control chromosomes (gnomAD). c.1948G>A has been reported in the literature in multiple individuals affected with Hereditary Spastic Paraplegia 7 and the variant co-segregated with the disease (Fogel_2014, Dela Casa-Fages_2019, Fernndez-Moreno_2020, Charif_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33841295, 31433872, 32204931, 25133958). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=1), likely pathogenic (n=1) and pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 650 of the SPG7 protein (p.Asp650Asn). This variant is present in population databases (rs769602042, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 31433872, 32204931; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 220101). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SPG7 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 26, 2023 | - - |
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 24, 2022 | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to be associated with disease in at least one family, however, the available information does not rule out an apparent association due to chance. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. The variant is located in a region that is considered important for protein function and/or structure. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at