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NF1c.8085A>GUncertain significance
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Variant interpretation report

NF1 c.8085A>G, p.(Gly2695=)

NM_000267.3:c.8085A>G NP_000258.1:p.(Gly2695=) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About NF1

No gene-level summary was recorded for this case.

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 ClinGen NF1 VCEP v1.0.0. 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: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 and gnomAD v4.1 (observed frequency 0 in both datasets), which is below the PM2 rarity threshold of 0.1% and supports rarity in the general population.

Benign criteria applied · 1
BP7Supporting
BP7 · supporting

This is a synonymous NF1 variant, p.(Gly2695=), and SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, supporting that the change is unlikely to alter the protein or RNA product.

Recorded classification: Uncertain significance

Neurofibromatosis and Schwannomatosis Specification v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback.

02The sources

Evidence at a glance

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

No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · BP7 →
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed

No COSMIC evidence statement is recorded in this case.

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 ClinGen NF1 VCEP v1.0.0, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 3 not met · 15 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The NF1 c.8085A>G (p.(Gly2695=)) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, with an observed population frequency of 0 in both datasets, which is below the PM2 rarity threshold of 0.1%.

This is a synonymous change, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which supports BP7 and argues against a predicted RNA effect.

Met · 2

PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1 (observed frequency 0 in both datasets), which is below the PM2 rarity threshold of 0.1% and supports rarity in the general population. Details ▾Hide ▴
Rule
PM2_Supporting applied for absence from population databases.
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗
BP7 SupportingThis is a synonymous NF1 variant, p.(Gly2695=), and SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, supporting that the change is unlikely to alter the protein or RNA product. Details ▾Hide ▴
Rule
BP7 applied for a synonymous variant with no predicted splice impact.
Evidence considered
  • The normalized protein consequence is p.(Gly2695=) / p.(G2695=).
  • SpliceAI predicts no significant splice impact with max delta score 0.01.
Sources
spliceai ↗cspec ↗

Not met · 3 · evaluated, threshold not reached

PP3 Computational evidence does not support a deleterious effect because this synonymous variant has a SpliceAI maximum delta score of 0.01, which predicts no significant splice impact. Details ▾Hide ▴
Rule
PP3 not met because in silico evidence does not support a damaging effect.
Evidence considered
  • SpliceAI predicts no significant splice impact with max delta score 0.01.
Sources
spliceai ↗
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 (observed frequency 0 in both datasets), which is below the BA1 benign threshold of >1%. Details ▾Hide ▴
Rule
BA1 not met because population frequency is well below the benign stand-alone threshold.
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 (observed frequency 0 in both datasets), which is below the BS1 benign threshold of >0.3%. Details ▾Hide ▴
Rule
BS1 not met because population frequency is below the benign threshold.
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 15 · no assessment recorded

PS2 No confirmed de novo occurrence with verified parental relationships was identified, so PS2 cannot be assessed from the available evidence. Details ▾Hide ▴
Still missing
  • Confirmed de novo testing with parental relationships and phenotype information.
PS3 No well-established functional studies demonstrating a damaging effect for this specific variant were identified. Details ▾Hide ▴
Still missing
  • Variant-specific validated functional assay data.
PS4 No case-control or prevalence data showing enrichment of this variant in affected individuals were identified. Details ▾Hide ▴
Evidence considered
  • This variant is absent from ClinVar.
Still missing
  • Published or curated affected-case counts with appropriate control comparison.
Sources
clinvar ↗
PM1 Available evidence does not establish that this synonymous variant lies in a mutational hotspot or a critical functional domain without benign variation. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots did not identify a statistically significant hotspot at Gly2695.
Still missing
  • Authoritative NF1 domain or hotspot evidence specific to this codon.
Sources
hotspots ↗
PM3 No phase data or observations in trans with a pathogenic variant were identified. Details ▾Hide ▴
Still missing
  • Segregation and phase data if relevant.
PM6 No assumed de novo occurrence without full parental confirmation was identified. Details ▾Hide ▴
Still missing
  • Reported de novo occurrence data.
PP1 No segregation data were identified for this variant in affected family members. Details ▾Hide ▴
Still missing
  • Family segregation studies.
PP4 No phenotype or family history information specific enough to support a highly NF1-specific clinical presentation was provided. Details ▾Hide ▴
Still missing
  • Detailed phenotype
  • diagnostic features
  • and family history.
PP5 No reputable source classification supporting pathogenicity was identified for this variant. Details ▾Hide ▴
Evidence considered
  • This variant is absent from ClinVar.
Still missing
  • Independent reputable-source pathogenic classification if available.
Sources
clinvar ↗
BS2 No evidence was identified showing this variant in healthy adult individuals at a frequency inconsistent with NF1 pathogenicity. Details ▾Hide ▴
Still missing
  • Well-phenotyped unaffected carrier data.
BS3 No well-established functional studies demonstrating a benign effect for this specific variant were identified. Details ▾Hide ▴
Still missing
  • Variant-specific validated benign functional assay data.
BS4 No family data showing lack of segregation with disease were identified. Details ▾Hide ▴
Still missing
  • Family segregation data demonstrating non-segregation.
BP2 No phase data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant. Details ▾Hide ▴
Still missing
  • Phase data with another pathogenic variant.
BP5 No alternate molecular diagnosis or other cause explaining the phenotype was identified. Details ▾Hide ▴
Still missing
  • Comprehensive phenotype review and alternate diagnosis assessment.
BP6 No reputable source classification supporting a benign interpretation was identified for this variant. Details ▾Hide ▴
Evidence considered
  • This variant is absent from ClinVar.
Still missing
  • Independent reputable-source benign classification if available.
Sources
clinvar ↗
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANF1 loss of function is an established disease mechanism, but this variant is a synonymous substitution and is not a nonsense, frameshift, or canonical ±1,2 splice-site change, so PVS1 does not apply. Details ▾Hide ▴
Rule
Generic PVS1 framework not applicable to a synonymous non-canonical splice variant.
Evidence considered
  • NF1 is eligible for generic PVS1 consideration because loss of function is an established germline disease mechanism.
  • NM_000267.3:c.8085A>G is classified in the generic PVS1 scaffold as 'other' and not a canonical splice-consensus variant.
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PS1 N/APS1 is intended for a variant that results in the same amino acid change as an established pathogenic variant; this variant is synonymous and no alternate pathogenic amino acid substitution was identified. Details ▾Hide ▴
Rule
PS1 does not apply to a synonymous variant without a matching pathogenic amino acid change.
Evidence considered
  • The normalized protein consequence is p.(Gly2695=) / p.(G2695=).
Sources
cspec ↗
PM4 N/APM4 applies to protein length changes from in-frame insertions, deletions, or stop-loss variants; this variant is a synonymous substitution and does not alter protein length. Details ▾Hide ▴
Rule
PM4 not applicable to a synonymous substitution.
Evidence considered
  • The normalized protein consequence is p.(Gly2695=) / p.(G2695=).
Sources
cspec ↗
PM5 N/APM5 is intended for a novel missense change at an amino acid residue where a different pathogenic missense change has been established; this variant is synonymous. Details ▾Hide ▴
Rule
PM5 not applicable to a synonymous variant.
Evidence considered
  • The normalized protein consequence is p.(Gly2695=) / p.(G2695=).
Sources
cspec ↗
PP2 N/APP2 is used for missense variants in genes with a low rate of benign missense variation and a common pathogenic missense mechanism; this variant is not missense. Details ▾Hide ▴
Rule
PP2 not applicable to a synonymous variant.
Evidence considered
  • The normalized protein consequence is synonymous.
Sources
cspec ↗
BP1 N/ABP1 applies to missense variants in genes where truncating variants are the predominant disease mechanism; this variant is synonymous and not missense. Details ▾Hide ▴
Rule
BP1 not applicable to a synonymous variant.
Evidence considered
  • The normalized protein consequence is synonymous.
Sources
cspec ↗
BP3 N/ABP3 applies to in-frame insertions or deletions in repetitive regions without known function; this variant is a synonymous single-nucleotide substitution. Details ▾Hide ▴
Rule
BP3 not applicable to a synonymous substitution.
Evidence considered
  • The variant is a single-nucleotide synonymous substitution.
Sources
cspec ↗
BP4 N/AFor this synonymous variant, benign computational evidence is more appropriately captured by BP7 rather than BP4. Details ▾Hide ▴
Rule
BP4 not separately applied because BP7 captures benign evidence for a synonymous variant.
Evidence considered
  • SpliceAI predicts no significant splice impact with max delta score 0.01.
Sources
spliceai ↗cspec ↗

Identifiers

Gene
NF1
Transcript
NM_000267.3
Coding (HGVS c.)
NM_000267.3:c.8085A>G
Protein (HGVS p.)
NP_000258.1:p.(Gly2695=)
GRCh38
chr17:31359003 A>G
GRCh37
chr17:29686021 A>G

Gene diagram

Every interpreted variant in NF1, mapped onto the exon structure of NM_000267.3. Select a row to find it on the plot.

NF1NM_000267.3
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP7 SupportingThis is a synonymous NF1 variant, p.(Gly2695=), and SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, supporting that the change is unlikely to alter the protein or RNA product. Details ▾Hide ▴
Rule
BP7 applied for a synonymous variant with no predicted splice impact.
Evidence considered
  • The normalized protein consequence is p.(Gly2695=) / p.(G2695=).
  • SpliceAI predicts no significant splice impact with max delta score 0.01.
Sources
spliceai ↗cspec ↗
PP3 Computational evidence does not support a deleterious effect because this synonymous variant has a SpliceAI maximum delta score of 0.01, which predicts no significant splice impact. Details ▾Hide ▴
Rule
PP3 not met because in silico evidence does not support a damaging effect.
Evidence considered
  • SpliceAI predicts no significant splice impact with max delta score 0.01.
Sources
spliceai ↗
BP4 N/AFor this synonymous variant, benign computational evidence is more appropriately captured by BP7 rather than BP4. Details ▾Hide ▴
Rule
BP4 not separately applied because BP7 captures benign evidence for a synonymous variant.
Evidence considered
  • SpliceAI predicts no significant splice impact with max delta score 0.01.
Sources
spliceai ↗cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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 Captured SpliceAI source record Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec 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 is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

Functional

OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).

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.