FBP1c.960delinsGGLikely pathogenic

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Variant interpretation report

FBP1 c.960delinsGG, p.(Ser321ValfsTer13)

NM_000507.4:c.960delinsGG NP_000498.2:p.(Ser321ValfsTer13) View identifiers

Classification

Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About FBP1

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 strong (pathogenic) · 2 supporting (pathogenic)
Expert rules: Not recorded
Other laboratories (ClinVar): 3 Pathogenic
Pipeline record: 12 Jun 2026

Evidence considered

View criteria

Applied evidence criteria

PVS1 (strong): 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.
PM2 (supporting): 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.
PP5 (supporting): 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.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 3 Benign evidence criteria: 0

Pathogenic criteria applied · 3

PVS1Strong

PVS1 · strong

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.

PM2Supporting

PM2 · supporting

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.

PP5Supporting

PP5 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 strong, PM2 supporting, PP5 supporting; combination = 1 strong + 2 supporting, which maps to Likely Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.070 maximum delta

Recorded SpliceAI maximum delta score: 0.070. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

3 reported laboratory submissions

3 Pathogenic.

Applied · PP5 → ClinVar ↗

No screenshot for this evidence

Functional evidence

Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 3 met · 15 not met · 2 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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).

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.

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

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.

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.

Met · 3

PVS1 StrongNM_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. Details ▾Hide ▴

Evidence considered

Frameshift variant (p.Ser321ValfsTer13) in FBP1 exon 7 (last exon of 7)
FBP1 loss of function is established mechanism for fructose-1
6-bisphosphatase deficiency
NMD escape predicted (last exon variant)
strength downgraded per PMC6185798
Variant absent from gnomAD v2.1 and v4.1

Still missing

No gene-specific PVS1 decision tree available for FBP1
generic framework applied

Sources

pvs1_generic_framework ↗gnomad_v2 ↗gnomad_v4 ↗clinvar ↗

PM2 SupportingNM_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. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (0 alleles)
Absent from gnomAD v4.1 (0 alleles)
Population frequency effectively 0%
well below 0.1% PM2 threshold

Sources

gnomad_v2 ↗gnomad_v4 ↗

PP5 SupportingNM_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. Details ▾Hide ▴

Evidence considered

ClinVar Variation ID 372364: Pathogenic classification
3 clinical laboratories: GeneDx (SCV000490526)
LabCorp (SCV003934589)
PreventionGenetics (SCV004754092)
Criteria provided by 2 of 3 submitters

Sources

clinvar ↗

Not met · 15 · evaluated, threshold not reached

PS2 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. Details ▾Hide ▴

Evidence considered

No de novo reports identified in literature or ClinVar

Still missing

No data on parental testing for probands carrying this variant

Sources

3468705828420223309277573714207631804789

PS4 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. Details ▾Hide ▴

Evidence considered

ClinVar classification as Pathogenic by 3 clinical laboratories (Variation ID 372364)
Absent from gnomAD population controls (v2.1 and v4.1)
No proband count or odds ratio data available

Still missing

No case-control study or proband counting data quantifying enrichment

Sources

clinvar ↗346870582842022330927757371420763180478939036704

PM1 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. Details ▾Hide ▴

Evidence considered

Cancer Hotspots: residue not statistically significant
No functional domain analysis identifying this as a critical region

Still missing

No FBP1-specific functional domain hotspot mapping available

PM6 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. Details ▾Hide ▴

Still missing

No de novo reports identified

Sources

3468705828420223309277573714207631804789

PP1 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. Details ▾Hide ▴

Still missing

No family studies with segregation data

Sources

3468705828420223

PP3 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score 0.07 (no predicted splice alteration)
REVEL not available for indel variants
BayesDel not available for indel variants

Still missing

No in silico tools designed for indel pathogenicity prediction available

Sources

spliceai ↗

PP4 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. Details ▾Hide ▴

Evidence considered

ClinVar clinical testing submissions consistent with FBP1 deficiency phenotype
Phenotype of hypoglycemia and lactic acidosis is nonspecific across metabolic disorders

Still missing

No detailed phenotype specificity data for the proband

Sources

clinvar ↗

BA1 NM_000507.4:c.960delinsGG is absent from gnomAD v2.1 and v4.1. BA1 requires an allele frequency above 1% in population databases. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (0 alleles)
Absent from gnomAD v4.1 (0 alleles)
Population frequency 0%
far below 1% BA1 threshold

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 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. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (0 alleles)
Absent from gnomAD v4.1 (0 alleles)
Population frequency 0%
far below 0.3% BS1 threshold

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 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. Details ▾Hide ▴

Evidence considered

Variant absent from gnomAD which includes predominantly healthy adult populations

Still missing

No documentation of this variant in healthy controls

BS4 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. Details ▾Hide ▴

Evidence considered

Variant absent from gnomAD v2.1 and v4.1

Sources

gnomad_v2 ↗gnomad_v4 ↗

BP2 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. Details ▾Hide ▴

Still missing

No phase information with other FBP1 variants

BP4 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta 0.07 (no splice alteration predicted)
REVEL not available for indels
BayesDel not available for indels

Still missing

No benign-predicting computational tools applicable to indel variants

Sources

spliceai ↗

BP5 No observation of this variant in a case with an alternate molecular basis for disease has been reported. Details ▾Hide ▴

Still missing

No case with alternate molecular diagnosis carrying this variant

BP6 No reputable source classifies NM_000507.4:c.960delinsGG as benign or likely benign. ClinVar records classify this variant as Pathogenic. Details ▾Hide ▴

Evidence considered

ClinVar classification is Pathogenic (not benign)

Sources

clinvar ↗

Not assessed · 2 · no assessment recorded

PS3 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. Details ▾Hide ▴

Still missing

No functional studies specifically testing the impact of c.960delinsGG on FBPase enzymatic activity
protein stability
or splicing

Sources

37142076

BS3 No well-established functional studies demonstrating no deleterious effect for NM_000507.4:c.960delinsGG identified. PMID:37142076 studies a different FBP1 variant. Details ▾Hide ▴

Still missing

No functional studies showing normal FBPase activity for this variant

Sources

37142076

Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 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. Details ▾Hide ▴

No further detail was recorded.

PM3 N/ATrivially skipped: no trans phase data with a second pathogenic FBP1 variant available for this case. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 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. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 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. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 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. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 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. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 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. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 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. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 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. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: FBP1
Transcript: NM_000507.4
Coding (HGVS c.): NM_000507.4:c.960delinsGG
Protein (HGVS p.): NP_000498.2:p.(Ser321ValfsTer13)
GRCh38: chr9:94603438 T>CC
GRCh37: chr9:97365720 T>CC
ClinVar: 372364

Gene diagram

Every interpreted variant in FBP1, mapped onto the exon structure of NM_000507.4. Select a row to find it on the plot.

FBP1NM_000507.4

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in FBP1 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +134 bp

0.020

SpliceAI acceptor gainat +302 bp

0.070

SpliceAI donor lossat -53 bp

0.000

SpliceAI donor gainat +372 bp

0.020

Pangolin splice lossmagnitude shown

-0.290

Pangolin splice gain

0.010

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI max delta score 0.07 (no predicted splice alteration)
REVEL not available for indel variants
BayesDel not available for indel variants

Still missing

No in silico tools designed for indel pathogenicity prediction available

Sources

spliceai ↗

Evidence considered

SpliceAI max delta 0.07 (no splice alteration predicted)
REVEL not available for indels
BayesDel not available for indels

Still missing

No benign-predicting computational tools applicable to indel variants

Sources

spliceai ↗

BP7 N/ABP7 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. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).

5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

A novel variant in the FBP1 gene causes fructose-1,6-bisphosphatase deficiency through increased ubiquitination.

Liang X et al. · 2023

No paper-specific finding is recorded.

PMID 37142076 ↗
Clinical and Molecular Characterization of Patients with Fructose 1,6-Bisphosphatase Deficiency.

Li N et al. · 2017

No paper-specific finding is recorded.

PMID 28420223 ↗
Fructose-1,6-bisphosphatase deficiency presented with complex febrile convulsion.

Lee H et al. · 2019

No paper-specific finding is recorded.

PMID 30927757 ↗
Fructose-1,6-Bisphosphatase Deficiency.

Adam MP et al. · 1993

No paper-specific finding is recorded.

PMID 31804789 ↗
Fructose-1,6-bisphosphatase deficiency causes fatty liver disease and requires long-term hepatic follow-up.

Gorce M et al. · 2022

No paper-specific finding is recorded.

PMID 34687058 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.070 Open source ↗

ClinVar 3 Pathogenic Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories). (ClinVarID = 372364)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.