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NF1c.4686A>GUncertain significance
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Variant interpretation report

NF1 c.4686A>G, p.(Glu1562=)

NM_000267.3:c.4686A>G NP_000258.1:p.(Glu1562=) 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: 0 Benign evidence criteria: 1
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 1
BP7Met
BP7

This variant is a synonymous change, p.(Glu1562=), and available splice prediction does not indicate a significant impact on RNA splicing. SpliceAI shows a maximum delta score of 0.01, which supports BP7.

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.

gnomAD v4.1
gnomAD v2.1
Population frequency
360 / 1,613,306 alleles

gnomAD v4.1: 360 / 1,613,306 alleles. Recorded AF 0.000223144. Recorded homozygote count 2.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000226663; MAF= 0.02267%, 64/282358 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000695217; MAF= 0.06952%, 5/7192 alleles, homozygotes = 0); grpmax FAF= 0.00031301.

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗
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: 1 met · 6 not met · 11 not assessed · 10 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.4686A>G (p.Glu1562=) variant has been reported in ClinVar predominantly as likely benign or benign, with some uncertain significance submissions.

This variant is present in population databases, including gnomAD v2.1 at an allele frequency of 0.000226663 (64/282358) and gnomAD v4.1 at an allele frequency of 0.000223144, which is below common benign strong thresholds but inconsistent with absence from controls.

In silico splice prediction does not support a splice-disrupting effect, with SpliceAI showing a maximum delta score of 0.01.

Met · 1

BP7 MetThis variant is a synonymous change, p.(Glu1562=), and available splice prediction does not indicate a significant impact on RNA splicing. SpliceAI shows a maximum delta score of 0.01, which supports BP7. Details ▾Hide ▴
Evidence considered
  • Protein consequence is p.(Glu1562=).
  • SpliceAI predicts no significant splice impact
  • max delta score 0.01.
Sources
spliceai ↗

Not met · 6 · evaluated, threshold not reached

PVS1 This variant is a synonymous change, p.(Glu1562=), and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants. Available evidence therefore does not support applying PVS1. Details ▾Hide ▴
Evidence considered
  • NF1 loss of function is an established disease mechanism at the gene level.
  • NM_000267.3:c.4686A>G is a synonymous variant and is not a canonical splice-site or truncating variant.
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PM1 This variant has not been identified in a mutational hotspot or well-established critical functional domain without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at this residue. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots review found no statistically significant hotspot for NF1 residue E1562.
Sources
hotspots ↗
PM2 This variant is present in population databases and is not absent or extremely rare. In gnomAD v2.1 the allele frequency is 0.000226663 (64/282358), and in gnomAD v4.1 the allele frequency is 0.000223144; these observations do not support PM2. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 total AF 0.000226663
  • 64/282358 alleles
  • 0 homozygotes.
  • gnomAD v4.1 total AF 0.000223144.
Sources
gnomad_v2 ↗gnomad_v4 ↗
PP3 Available computational evidence does not support a deleterious effect on splicing. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01. Details ▾Hide ▴
Evidence considered
  • SpliceAI DS_AG 0.00
  • DS_AL 0.01
  • DS_DG 0.00
  • DS_DL 0.00
  • max delta score 0.01.
Sources
spliceai ↗
BA1 Population frequency does not meet a stand-alone benign threshold. The allele frequency is 0.000226663 in gnomAD v2.1 and 0.000223144 in gnomAD v4.1, both well below the 0.01 threshold for BA1. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 total AF 0.000226663.
  • gnomAD v4.1 total AF 0.000223144.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 Population frequency is below the usual benign strong threshold. The allele frequency is 0.000226663 in gnomAD v2.1 and 0.000223144 in gnomAD v4.1, both below the 0.003 threshold, so BS1 is not met. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 total AF 0.000226663
  • highest subpopulation AF 0.000695217.
  • gnomAD v4.1 total AF 0.000223144
  • highest subpopulation AF 0.000449790.
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 11 · no assessment recorded

PS2 No confirmed de novo occurrence with verified maternity and paternity was identified. Available evidence does not support PS2. Details ▾Hide ▴
Still missing
  • No de novo case-level data were identified.
PS3 No well-established functional study demonstrating a damaging effect of this specific variant was identified. Available evidence does not support PS3. Details ▾Hide ▴
Still missing
  • No variant-specific functional assay was identified.
PS4 No case-control enrichment or sufficiently specific case series for this exact variant were identified. Available evidence does not support PS4. Details ▾Hide ▴
Still missing
  • No quantified enrichment data for this exact variant were identified.
PM6 No assumed de novo occurrence data for this exact variant were identified. Available evidence does not support PM6. Details ▾Hide ▴
Still missing
  • No de novo report without full parental confirmation was identified.
PP1 No segregation data were identified for this variant. Available evidence does not support PP1. Details ▾Hide ▴
Still missing
  • No informative family segregation data were identified.
PP4 No phenotype or family-history data specific enough to support PP4 were identified. Available evidence does not support PP4. Details ▾Hide ▴
Still missing
  • No phenotype-specific clinical correlation was identified.
BS2 Although this variant is present in population databases, no direct evidence was identified showing the variant in a sufficient number of well-phenotyped unaffected individuals for BS2. Available evidence does not support BS2. Details ▾Hide ▴
Evidence considered
  • Variant is present in gnomAD
  • but phenotype status of carriers is not established for BS2.
Still missing
  • No unaffected adult cohort data specific to this variant were identified.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established functional study demonstrating no damaging effect of this specific variant was identified. Available evidence does not support BS3. Details ▾Hide ▴
Still missing
  • No variant-specific benign functional assay was identified.
BS4 No segregation studies showing lack of segregation with disease were identified. Available evidence does not support BS4. Details ▾Hide ▴
Still missing
  • No informative non-segregation data were identified.
BP2 No phase data or observations with another pathogenic variant were identified. Available evidence does not support BP2. Details ▾Hide ▴
Still missing
  • No cis/trans phase information was identified.
BP5 No evidence was identified showing that the observed phenotype is fully explained by an alternate molecular diagnosis. Available evidence does not support BP5. Details ▾Hide ▴
Still missing
  • No alternate-molecular-diagnosis data were identified.
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThis variant is synonymous and does not create the same amino acid change as a known pathogenic variant. PS1 is not applicable. Details ▾Hide ▴
Evidence considered
  • Protein consequence is p.(Glu1562=).
PM3 N/APM3 is intended for recessive disorders with trans observations. NF1 is evaluated here in an autosomal dominant disease context, so PM3 is not applicable. Details ▾Hide ▴
Evidence considered
  • NF1 specification page lists autosomal dominant inheritance.
Sources
cspec ↗
PM4 N/AThis variant is not a protein length-changing in-frame deletion, insertion, or stop-loss variant. PM4 is not applicable. Details ▾Hide ▴
Evidence considered
  • Protein consequence is synonymous
  • p.(Glu1562=).
PM5 N/AThis variant is synonymous and does not represent a novel missense change at an amino acid residue where another pathogenic missense change has been established. PM5 is not applicable. Details ▾Hide ▴
Evidence considered
  • Protein consequence is p.(Glu1562=).
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation and where missense is a common disease mechanism. This variant is not missense, so PP2 is not applicable. Details ▾Hide ▴
Evidence considered
  • Protein consequence is synonymous
  • not missense.
PP5 N/APP5 was not used. Existing database classifications alone were not treated as independent pathogenic evidence for this adjudication. Details ▾Hide ▴
Evidence considered
  • ClinVar contains non-unanimous submissions for this variant.
Sources
clinvar ↗
BP1 N/ABP1 applies to certain missense variants in genes where truncating variants are the predominant mechanism. This variant is not missense, so BP1 is not applicable. Details ▾Hide ▴
Evidence considered
  • Protein consequence is synonymous
  • not missense.
BP3 N/ABP3 applies to in-frame variants in repetitive regions without known function. This variant is a synonymous substitution, so BP3 is not applicable. Details ▾Hide ▴
Evidence considered
  • Variant type is synonymous substitution.
BP4 N/AFor this synonymous variant, benign computational evidence is better captured under BP7 rather than BP4. BP4 was not applied separately. Details ▾Hide ▴
Evidence considered
  • SpliceAI predicts no significant splice impact.
Sources
spliceai ↗
BP6 N/ABP6 was not used. Existing ClinVar assertions were considered supportive context only and were not treated as independent benign evidence in this adjudication. Details ▾Hide ▴
Evidence considered
  • ClinVar shows predominantly likely benign and benign submissions
  • but this criterion was not applied independently.
Sources
clinvar ↗

Identifiers

Gene
NF1
Transcript
NM_000267.3
Coding (HGVS c.)
NM_000267.3:c.4686A>G
Protein (HGVS p.)
NP_000258.1:p.(Glu1562=)
GRCh38
chr17:31265253 A>G
GRCh37
chr17:29592271 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 v4.1 360 / 1,613,306 alleles AF 0.000223 · 2 homozygotes · FAF 0.000317
gnomAD v2.1 64 / 282,358 alleles AF 0.000227 · 0 homozygotes · FAF 0.000313

By genetic ancestry

gnomAD v4.1

AF 0.00022 · 360 / 1,613,306 alleles · 2 hom · FAF 0.00032
Admixed American27 / 60,028 0.000451 hom
European (non-Finnish)302 / 1,179,438 0.000261 hom
Remaining individuals14 / 62,448 0.00022
European (Finnish)14 / 64,004 0.00022
African/African American2 / 75,012 2.7e-05
South Asian1 / 91,064 1.1e-05
0 alternate alleles recorded in 4 other groups: Amish, East Asian, Middle Eastern, Ashkenazi Jewish.

gnomAD v2.1

AF 0.00023 · 64 / 282,358 alleles · 0 hom · FAF 0.00031
Remaining individuals5 / 7,192 0.0007
Admixed American17 / 35,418 0.00048
European (Finnish)7 / 25,120 0.00028
European (non-Finnish)34 / 128,982 0.00026
African/African American1 / 24,760 4e-05
0 alternate alleles recorded in 3 other groups: Ashkenazi Jewish, East Asian, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.000223144; MAF= 0.02231%, 360/1613306 alleles, homozygotes = 2) and has highest observed frequency in the Admixed American population (AF= 0.00044979; MAF= 0.04498%, 27/60028 alleles, homozygotes = 1); grpmax FAF= 0.00031689.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000226663; MAF= 0.02267%, 64/282358 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000695217; MAF= 0.06952%, 5/7192 alleles, homozygotes = 0); grpmax FAF= 0.00031301.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP7 MetThis variant is a synonymous change, p.(Glu1562=), and available splice prediction does not indicate a significant impact on RNA splicing. SpliceAI shows a maximum delta score of 0.01, which supports BP7. Details ▾Hide ▴
Evidence considered
  • Protein consequence is p.(Glu1562=).
  • SpliceAI predicts no significant splice impact
  • max delta score 0.01.
Sources
spliceai ↗
PP3 Available computational evidence does not support a deleterious effect on splicing. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01. Details ▾Hide ▴
Evidence considered
  • SpliceAI DS_AG 0.00
  • DS_AL 0.01
  • DS_DG 0.00
  • DS_DL 0.00
  • max delta score 0.01.
Sources
spliceai ↗
BP4 N/AFor this synonymous variant, benign computational evidence is better captured under BP7 rather than BP4. BP4 was not applied separately. Details ▾Hide ▴
Evidence considered
  • SpliceAI predicts no significant splice impact.
Sources
spliceai ↗

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 v4.1 360 / 1,613,306 recorded alleles 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

This variant is present in gnomAD v4.1 (AF= 0.000223144; MAF= 0.02231%, 360/1613306 alleles, homozygotes = 2) and has highest observed frequency in the Admixed American population (AF= 0.00044979; MAF= 0.04498%, 27/60028 alleles, homozygotes = 1); grpmax FAF= 0.00031689.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000226663; MAF= 0.02267%, 64/282358 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000695217; MAF= 0.06952%, 5/7192 alleles, homozygotes = 0); grpmax FAF= 0.00031301.

ClinVar

This variant has been reported in ClinVar as Likely benign (7 clinical laboratories) and as Uncertain significance (3 clinical laboratories) and as Benign (2 clinical laboratories).

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.