Variant classification summary

NM_000507.4:c.960delinsGG

FBP1 · NP_000498.2:p.(Ser321ValfsTer13) · NM_000507.4

GRCh37: chr9:97365720 T>CC · GRCh38: chr9:94603438 T>CC

Gene: FBP1 Transcript: NM_000507.4

Final call

Likely Pathogenic

PVS1 strong PM2 supporting PP5 supporting

Variant details

Gene

FBP1

Transcript

NM_000507.4

Protein

NP_000498.2:p.(Ser321ValfsTer13)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000507.4:c.960delinsGG (p.Ser321ValfsTer13) is a frameshift variant in exon 7 (last exon) of FBP1, where loss of function is an established mechanism for fructose-1,6-bisphosphatase deficiency (PVS1 at strong strength, downgraded from very strong due to predicted NMD escape per PMC6185798).

2

The variant is absent from gnomAD v2.1 and v4.1 population databases (0 alleles out of >1.6 million), supporting PM2 at supporting strength.

3

This variant has been classified as Pathogenic by three clinical laboratories in ClinVar (Variation ID 372364), meeting PP5 at supporting strength.

4

SpliceAI predicts no significant splice impact (max delta score 0.07), and in silico pathogenicity scores are not applicable to this indel variant. PP3 and BP4 are not met.

5

Under generic ACMG/AMP 2015 combination rules (PMID:25741868), one strong criterion (PVS1) and two supporting criteria (PM2, PP5) yields a classification of Likely Pathogenic.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	Met	NM_000507.4:c.960delinsGG is a frameshift variant (p.Ser321ValfsTer13) in exon 7 of FBP1, where loss of function is an established mechanism for fructose-1,6-bisphosphatase deficiency (autosomal recessive). Under the ClinGen SVI PVS1 framework (PMC6185798), the variant occurs in the last exon and is predicted to escape nonsense-mediated decay, warranting a downgrade from very_strong to strong.	pvs1_generic_framework gnomad_v2 gnomad_v4 clinvar
PS1	N/A	PS1 applies to single nucleotide variants producing the same amino acid change as an established pathogenic missense variant. NM_000507.4:c.960delinsGG is an indel (frameshift), not a single nucleotide substitution.
PS2	Not met	No de novo observation with confirmed maternity and paternity reported for this variant. FBP1 deficiency is an autosomal recessive disorder in which de novo occurrence is not the typical disease mechanism.
PS3	Not assessed	No well-established functional assay data specific to NM_000507.4:c.960delinsGG identified. PMID:37142076 describes functional characterization of a novel FBP1 variant via ubiquitination assays, but the variant studied is not c.960delinsGG.
PS4	Not met	No case-control data or statistically significant enrichment in affected individuals versus controls is available for this variant. While the variant has been reported as Pathogenic in ClinVar by three clinical laboratories, specific proband counts and phenotype details are not provided.	clinvar
PS5	N/A	PS5 requires PM5 to be met first (novel missense at same amino acid residue as a different established pathogenic missense). PM5 is not applicable for this indel variant.
PM1	Not met	The variant does not lie in a known mutational hotspot or critical functional domain without benign variation. Cancer Hotspots analysis was negative for statistical significance.
PM2	Met	NM_000507.4:c.960delinsGG is absent from gnomAD v2.1 and v4.1 population databases (0 alleles out of >1.6 million total alleles). Under generic ACMG/AMP rules, PM2 applies at supporting strength for variants with population frequency below 0.1% and absent from large population databases.	gnomad_v2 gnomad_v4
PM3	N/A	Trivially skipped: no trans phase data with a second pathogenic FBP1 variant available for this case.
PM4	N/A	PM4 applies to in-frame deletions/insertions in non-repeat regions and stop-loss variants. NM_000507.4:c.960delinsGG is an out-of-frame frameshift variant; its null effect is captured by PVS1.
PM5	N/A	PM5 applies to missense variants at the same amino acid residue as a different known pathogenic missense change. NM_000507.4:c.960delinsGG is an indel (frameshift), not a missense variant. Same-residue PM5 semantics cannot be resolved for this indel.
PM6	Not met	No assumed de novo observation (without confirmation of parentage) reported for this variant. FBP1 deficiency is autosomal recessive, making de novo occurrence an unlikely disease mechanism.
PP1	Not met	No co-segregation data in affected families is available for this variant. Co-segregation analysis requires multiple affected family members carrying the variant, which has not been reported for c.960delinsGG.
PP2	N/A	PP2 applies to missense variants in genes where missense variation is a common disease mechanism and benign missense variation is rare. NM_000507.4:c.960delinsGG is an indel, not a missense variant.
PP3	Not met	SpliceAI max delta score is 0.07, indicating no significant splice impact. REVEL and BayesDel in silico scores are not available for indels. Multiple lines of computational evidence do not support a deleterious effect.	spliceai
PP4	Not met	While the affected individual's phenotype (hypoglycemia, lactic acidosis) is consistent with fructose-1,6-bisphosphatase deficiency, these symptoms are nonspecific and overlap with many other inborn errors of metabolism. A single case with a nonspecific presentation does not meet PP4.	clinvar
PP5	Met	NM_000507.4:c.960delinsGG has been reported as Pathogenic in ClinVar (Variation ID 372364) by three clinical laboratories (GeneDx, LabCorp, PreventionGenetics), with criteria provided by at least two submitters. This represents a consensus classification from reputable clinical sources.	clinvar
BA1	Not met	NM_000507.4:c.960delinsGG is absent from gnomAD v2.1 and v4.1. BA1 requires an allele frequency above 1% in population databases.	gnomad_v2 gnomad_v4
BS1	Not met	NM_000507.4:c.960delinsGG is absent from gnomAD v2.1 and v4.1. BS1 requires an allele frequency above 0.3% in population databases.	gnomad_v2 gnomad_v4
BS2	Not met	No observation of this variant in a healthy adult individual has been documented. For a fully penetrant recessive disorder, BS2 requires the variant to be observed in trans with a pathogenic variant or in a homozygous state in a healthy adult.
BS3	Not assessed	No well-established functional studies demonstrating no deleterious effect for NM_000507.4:c.960delinsGG identified. PMID:37142076 studies a different FBP1 variant.
BS4	Not met	No observation of NM_000507.4:c.960delinsGG in a healthy adult individual has been reported. The variant is absent from gnomAD. BS4 requires presence of the variant in a healthy adult for a fully penetrant disorder.	gnomad_v2 gnomad_v4
BP1	N/A	BP1 applies to missense variants in genes where a pathogenic truncating variant is known and the primary disease mechanism requires truncation. NM_000507.4:c.960delinsGG is itself a truncating (frameshift) variant, not a missense.
BP2	Not met	No observation of this variant in trans with a pathogenic variant in a gene for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern. No phase data available.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function. NM_000507.4:c.960delinsGG is an out-of-frame frameshift variant, not an in-frame indel.
BP4	Not met	SpliceAI max delta score is 0.07, indicating no significant splice impact. However, BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. REVEL and BayesDel are not available for indels, so computational evidence is neutral rather than supporting a benign interpretation.	spliceai
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease has been reported.
BP6	Not met	No reputable source classifies NM_000507.4:c.960delinsGG as benign or likely benign. ClinVar records classify this variant as Pathogenic.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted impact on splicing. NM_000507.4:c.960delinsGG is an indel variant causing a frameshift, not a synonymous change.

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