Variant classification summary

NM_025137.4:c.6062G>A

SPG11 · NP_079413.3:p.(Arg2021Gln) · NM_025137.4

GRCh37: chr15:44865888 C>T · GRCh38: chr15:44573690 C>T

Gene: SPG11 Transcript: NM_025137.4

Final call

VUS

PM2 moderate BP4 supporting

Variant details

Gene

SPG11

Transcript

NM_025137.4

Protein

NP_079413.3:p.(Arg2021Gln)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The SPG11 c.6062G>A (p.Arg2021Gln) variant has been reported in ClinVar with one likely benign submission and one uncertain significance submission.

2

This variant is rare in population databases, with the highest observed frequency in East Asian individuals of 0.09023% in gnomAD v2.1 and 0.05125% in gnomAD v4.1, both below the 0.1% PM2 threshold used for this generic non-VCEP review.

3

Computational data argue against a damaging effect, with REVEL 0.113, BayesDel -0.445237, and SpliceAI showing no significant predicted splice impact with a maximum delta score of 0.02.

Final determination: Generic ACMG/AMP 2015 fallback rules identified both pathogenic and benign evidence, so the overall classification remains Variant of Uncertain Significance because the evidence is conflicting.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	SPG11 loss of function is an established disease mechanism, but this variant is a missense substitution, p.(Arg2021Gln), and does not fall into the generic PVS1 null-variant categories. Available splice data do not indicate a loss-of-function splicing effect, so PVS1 is not applicable.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified showing that a different nucleotide change causing the same amino acid substitution has already been established as pathogenic or likely pathogenic, so PS1 was not assessed.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with parental confirmation was identified for this variant, so PS2 was not assessed.	clinvar
PS3	Not assessed	No well-established functional studies were identified showing a damaging effect of p.(Arg2021Gln), so PS3 was not assessed.	oncokb PMID:25741868
PS4	Not met	Available evidence does not show enrichment of this variant in affected individuals compared with controls. The variant has limited ClinVar submissions and no case-control or prevalence data sufficient for PS4 were identified.	clinvar
PM1	Not met	This variant has not been shown to lie in a well-established critical functional domain or statistically significant mutational hotspot. Cancer Hotspots did not identify a hotspot at residue Arg2021.	hotspots
PM2	Met	This variant is rare in population databases. In gnomAD v2.1, the highest observed population frequency was 0.09023% in East Asian individuals, and in gnomAD v4.1 it was 0.05125% in East Asian individuals; both are below the 0.1% PM2 threshold used for this generic non-VCEP review.	gnomad_v2 gnomad_v4
PM3	Not assessed	No case-level evidence was identified showing this variant in trans with a pathogenic or likely pathogenic SPG11 variant in an affected individual, so PM3 was not assessed.	clinvar
PM4	N/A	This is a missense substitution and does not cause a protein length change, so PM4 is not applicable.
PM5	Not assessed	No evidence was identified showing a different pathogenic missense change at codon 2021, so PM5 was not assessed.	clinvar
PM6	Not assessed	No presumed de novo occurrence without full parental confirmation was identified for this variant, so PM6 was not assessed.	clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not assessed.	clinvar
PP2	Not assessed	Available evidence was insufficient to show that SPG11 is a gene in which missense variation is a common disease mechanism and benign missense variation is uncommon, so PP2 was not assessed.	pvs1_gene_context
PP3	Not met	Available computational evidence does not support a damaging effect. REVEL was 0.113, BayesDel was -0.445237, and SpliceAI predicted no significant splice impact with a maximum delta score of 0.02, so PP3 was not met.	revel bayesdel spliceai
PP4	Not assessed	No phenotype-specific clinical data were available to determine whether the observed presentation is highly specific for SPG11-related disease, so PP4 was not assessed.
PP5	N/A	PP5 was not used in this review because assertion-only evidence from external classifications is not considered sufficient for criterion application.	clinvar
BA1	Not met	The population frequency is well below the 1% BA1 threshold. The highest observed population frequency was 0.09023% in gnomAD v2.1 East Asian individuals and 0.05125% in gnomAD v4.1 East Asian individuals.	gnomad_v2 gnomad_v4
BS1	Not met	The population frequency is below the 0.3% BS1 threshold used for this generic non-VCEP review. The highest observed population frequency was 0.09023% in gnomAD v2.1 East Asian individuals and 0.05125% in gnomAD v4.1 East Asian individuals.	gnomad_v2 gnomad_v4
BS2	Not met	This variant was not observed in homozygous state in the reviewed population data, and no evidence was identified showing the full disease-relevant genotype in healthy individuals, so BS2 was not met.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional studies were identified showing normal function for p.(Arg2021Gln), so BS3 was not assessed.	oncokb PMID:25741868
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 was not assessed.	clinvar
BP1	Not assessed	SPG11 loss of function is a known disease mechanism, but the available evidence was insufficient to conclude that missense variants are generally not disease-causing in this gene, so BP1 was not assessed.	pvs1_gene_context
BP2	Not assessed	No phase information was identified showing this variant in cis with a pathogenic variant or in trans in a context supporting BP2, so BP2 was not assessed.	clinvar
BP3	N/A	This variant is not an in-frame insertion or deletion in a repetitive region, so BP3 is not applicable.
BP4	Met	Multiple computational results support a benign interpretation. REVEL was 0.113, BayesDel was -0.445237, and SpliceAI predicted no significant splice impact with a maximum delta score of 0.02, which together argue against a damaging protein or splice effect.	revel bayesdel spliceai
BP5	Not assessed	No evidence was identified for an alternate molecular explanation for the phenotype independent of this variant, so BP5 was not assessed.
BP6	N/A	BP6 was not used in this review because assertion-only benign classifications from external sources are not considered sufficient for criterion application.	clinvar
BP7	N/A	This variant is missense rather than synonymous and does not meet the sequence context for BP7, so BP7 is not applicable.

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