NF1c.2747A>GUncertain significance

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Variant interpretation report

NF1 c.2747A>G, p.(Asn916Ser)

NM_000267.3:c.2747A>G NP_000258.1:p.(Asn916Ser) 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: 0

Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

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

92 / 1,613,808 alleles

gnomAD v4.1: 92 / 1,613,808 alleles. Recorded AF 5.7008e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 2.38928e-05; MAF= 0.00239%, 6/251122 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.2897e-05; MAF= 0.00529%, 6/113428 alleles, homozygotes = 0); grpmax FAF= 2.298e-05.

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.

No listed criterion applied

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: NF1, a negative regulator of RAS, is inactivated by mutation or deletion in various solid and hematologic malignancies.

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.

27 criteria with recorded statuses: 0 met · 9 not met · 12 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

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

Benign

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

Met Not met Not assessed Not applicable

The NF1 c.2747A>G (p.Asn916Ser) variant has been reported in ClinVar with conflicting germline classifications, including uncertain significance and likely benign, and without an expert panel assertion.

This variant is present at low frequency in population databases: gnomAD v4.1 shows an allele frequency of 0.00570% (92/1613808 alleles; grpmax FAF 0.006229%) and gnomAD v2.1 shows an allele frequency of 0.00239% (6/251122 alleles), which is below benign frequency thresholds but means the variant is not absent from controls.

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, so in silico splicing evidence does not independently support pathogenicity.

Not met · 9 · evaluated, threshold not reached

PS1 No evidence was identified that this amino acid change has been established as the same pathogenic amino acid substitution caused by a different nucleotide change. Details ▾Hide ▴

Evidence considered

ClinVar entry reviewed for the current variant and related residue-level context

Sources

clinvar ↗

PS4 Available evidence does not show enrichment of this variant in affected individuals over controls, and no case-control or multiple independent affected-case data were identified. Details ▾Hide ▴

Evidence considered

ClinVar shows conflicting clinical classifications without case-control enrichment evidence

Still missing

Affected-case counts and control comparison data

Sources

clinvar ↗

PM1 This variant has not been shown to lie in an established mutational hotspot or a well-characterized critical functional domain without benign variation. Details ▾Hide ▴

Evidence considered

Cancer Hotspots review did not identify a statistically significant hotspot at N916

Still missing

Residue- or domain-level evidence establishing a critical region for NF1 at codon 916

Sources

hotspots ↗

PM2 This variant is present in population databases and therefore is not absent from controls. In gnomAD v4.1 the overall allele frequency is 0.00570% (92/1613808) with grpmax FAF 0.006229%, and in gnomAD v2.1 the overall allele frequency is 0.00239% (6/251122). Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AF 5.7008e-05
92/1613808 alleles
grpmax FAF 6.229e-05
gnomAD v2.1 AF 2.38928e-05
6/251122 alleles

Sources

gnomad_v2 ↗gnomad_v4 ↗

PM5 Other missense substitutions at codon 916 were identified, but no pathogenic or likely pathogenic missense change at this residue was established to support PM5. Details ▾Hide ▴

Evidence considered

ClinVar residue-level review did not identify an established pathogenic missense substitution at codon 916

Still missing

A pathogenic or likely pathogenic missense variant affecting the same codon

Sources

clinvar ↗

PP3 Available computational evidence does not reach a level that independently supports a deleterious effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score 0.01 predicts no significant splice impact

Still missing

Gene-specific validated computational thresholds supporting pathogenic prediction

Sources

spliceai ↗

BA1 Population frequency is well below a benign stand-alone threshold. In gnomAD v4.1 the overall allele frequency is 0.00570% and the highest population frequency is 0.00754%, both far below 1%. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 total AF 5.7008e-05
gnomAD v4.1 highest population AF 7.54351e-05

Sources

gnomad_v4 ↗

BS1 Population frequency is below a benign strong threshold. In gnomAD v4.1 the overall allele frequency is 0.00570% and the highest population frequency is 0.00754%, both below 0.3%. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 total AF 5.7008e-05
gnomAD v4.1 highest population AF 7.54351e-05

Sources

gnomad_v4 ↗

BP4 Available computational evidence does not provide independent support for a benign effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, but this alone is insufficient to establish BP4 for a missense change. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score 0.01 predicts no significant splice impact

Still missing

Gene-specific validated computational thresholds supporting benign prediction

Sources

spliceai ↗

Not assessed · 12 · no assessment recorded

PS2 No confirmed de novo data with parental testing were identified. Details ▾Hide ▴

Still missing

Documented maternity and paternity testing

PS3 No well-established functional studies demonstrating a damaging effect of this specific variant were identified. Details ▾Hide ▴

Evidence considered

OncoKB has not reviewed this specific variant

Still missing

Validated functional assay data for NF1 p.Asn916Ser

Sources

oncokb ↗

PM6 No assumed de novo occurrence without confirmed parental testing was identified. Details ▾Hide ▴

Still missing

Documented de novo occurrence data

PP1 No segregation data were identified for this variant. Details ▾Hide ▴

Still missing

Family segregation data

PP2 Available evidence does not establish that missense variation in NF1 is sufficiently constrained in a way that supports applying PP2 to this variant. Details ▾Hide ▴

Evidence considered

No explicit local NF1 criterion rule for PP2 was available

Still missing

Gene-specific missense constraint rule supporting PP2

Sources

cspec ↗

PP4 No phenotype or family-history data were provided that would be sufficiently specific to NF1 for PP4 assessment. Details ▾Hide ▴

Still missing

Detailed phenotype and family-history information

BS2 No evidence was identified showing this variant in well-phenotyped unaffected individuals at an age appropriate for the disorder. Details ▾Hide ▴

Still missing

Confirmed unaffected adult carriers

BS3 No well-established functional studies demonstrating a benign effect of this specific variant were identified. Details ▾Hide ▴

Evidence considered

No variant-specific functional review was available in OncoKB

Still missing

Validated functional assay data showing no damaging effect

Sources

oncokb ↗

BS4 No family data were identified showing lack of segregation with disease. Details ▾Hide ▴

Still missing

Segregation data demonstrating non-segregation

BP1 Available evidence does not support applying BP1 to this NF1 missense variant. Details ▾Hide ▴

Evidence considered

No explicit local NF1 criterion rule for BP1 was available

Still missing

Gene-specific rule supporting BP1 for NF1 missense variants

Sources

cspec ↗

BP2 No phase data were identified showing this variant in trans with a pathogenic variant or in cis with another pathogenic variant. Details ▾Hide ▴

Still missing

Phase and co-occurrence data

BP5 No alternate molecular explanation for the phenotype was identified. Details ▾Hide ▴

Still missing

Comprehensive phenotype and alternate-cause evaluation

Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis is a missense variant, and available PVS1 assessment indicates it does not fall within the null-variant categories used for generic PVS1 application. Details ▾Hide ▴

Evidence considered

NF1 loss of function is an established disease mechanism
c.2747A>G is a missense change p.(Asn916Ser)
Generic PVS1 scaffold states the variant is outside default null-variant buckets

Sources

pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗

PM4 N/AThis variant is a missense substitution and does not produce a protein length change. Details ▾Hide ▴

Evidence considered

Protein consequence p.(Asn916Ser)

PP5 N/APP5 was not applied because external assertions without independently reviewable evidence are not used as standalone support. Details ▾Hide ▴

Evidence considered

ClinVar contains conflicting submitter classifications

Sources

clinvar ↗

BP3 N/ABP3 is intended for in-frame insertions or deletions in repetitive regions and is not applicable to this missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP6 N/ABP6 was not applied because external assertions without independently reviewable evidence are not used as standalone support. Details ▾Hide ▴

Evidence considered

ClinVar contains mixed submitter classifications
including likely benign and uncertain significance

Sources

clinvar ↗

BP7 N/ABP7 is not applicable because this variant is not synonymous or intronic. Details ▾Hide ▴

Evidence considered

Protein consequence p.(Asn916Ser)

Identifiers

Gene: NF1
Transcript: NM_000267.3
Coding (HGVS c.): NM_000267.3:c.2747A>G
Protein (HGVS p.): NP_000258.1:p.(Asn916Ser)
GRCh38: chr17:31229362 A>G
GRCh37: chr17:29556380 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…

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 NF1 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 92 / 1,613,808 alleles AF 5.7e-05 · 0 homozygotes · FAF 6.23e-05

gnomAD v2.1 6 / 251,122 alleles AF 2.39e-05 · 0 homozygotes · FAF 2.3e-05

By genetic ancestry

gnomAD v4.1

AF 5.7e-05 · 92 / 1,613,808 alleles · 0 hom · FAF 6.2e-05

European (non-Finnish)89 / 1,179,822	7.5e-05
Remaining individuals2 / 62,470	3.2e-05
African/African American1 / 74,918	1.3e-05

0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.

gnomAD v2.1

AF 2.4e-05 · 6 / 251,122 alleles · 0 hom · FAF 2.3e-05

European (non-Finnish)6 / 113,428

5.3e-05

0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 5.7008e-05; MAF= 0.00570%, 92/1613808 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.54351e-05; MAF= 0.00754%, 89/1179822 alleles, homozygotes = 0); grpmax FAF= 6.229e-05.

gnomAD v2.1

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI max delta score 0.01 predicts no significant splice impact

Still missing

Gene-specific validated computational thresholds supporting pathogenic prediction

Sources

spliceai ↗

Evidence considered

SpliceAI max delta score 0.01 predicts no significant splice impact

Still missing

Gene-specific validated computational thresholds supporting benign prediction

Sources

spliceai ↗

BP7 N/ABP7 is not applicable because this variant is not synonymous or intronic. Details ▾Hide ▴

Evidence considered

Protein consequence p.(Asn916Ser)

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 92 / 1,613,808 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

gnomAD v2.1

ClinVar

This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Likely benign (2 clinical laboratories).

In silico

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

Functional

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV62223654, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.