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NF1c.369C>GLikely benign
Print report
Variant interpretation report

NF1 c.369C>G, p.(Thr123=)

NM_000267.3:c.369C>G NP_000258.1:p.(Thr123=) View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

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

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

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: 2
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 2
BS1Strong
BS1 · strong

Population frequency is above a benign-supporting threshold. In gnomAD, the East Asian allele frequency is 1.11791% in v2.1 and 1.22098% in v4.1, which is well above 0.3%, supporting that this variant is too common for a pathogenic NF1 variant.

BP7Supporting
BP7 · supporting

This is a synonymous variant, it is not a canonical splice-site change, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, supporting no expected effect on RNA splicing.

Recorded classification: Likely benign

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; applied criteria: BS1 strong benign, BP7 supporting benign; combination = no applied criteria, which maps to Likely Benign.

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
595 / 1,614,134 alleles

gnomAD v4.1: 595 / 1,614,134 alleles. Recorded AF 0.000368619. Recorded homozygote count 8.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000820623; MAF= 0.08206%, 232/282712 alleles, homozygotes = 3) and has highest observed frequency in the East Asian population (AF= 0.0111791; MAF= 1.11791%, 223/19948 alleles, homozygotes = 3); grpmax FAF= 0.00989917.

Applied · BS1 →
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 identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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 · 4 not met · 13 not assessed · 9 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.369C>G (p.Thr123=) variant has been reported in ClinVar, where benign and likely benign classifications predominate.

This variant is present in population databases at high frequency, including East Asian allele frequencies of 1.11791% in gnomAD v2.1 and 1.22098% in gnomAD v4.1, supporting BS1 and arguing against rarity-based pathogenic criteria.

This synonymous variant is predicted to have no significant splice impact by SpliceAI, with a maximum delta score of 0.00, supporting BP7 and not supporting PP3.

Met · 2

BS1 StrongPopulation frequency is above a benign-supporting threshold. In gnomAD, the East Asian allele frequency is 1.11791% in v2.1 and 1.22098% in v4.1, which is well above 0.3%, supporting that this variant is too common for a pathogenic NF1 variant. Details ▾Hide ▴
Evidence considered
  • gnomAD v2 East Asian AF 1.11791%
  • gnomAD v4 East Asian AF 1.22098%
  • Multiple homozygotes observed in gnomAD
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP7 SupportingThis is a synonymous variant, it is not a canonical splice-site change, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, supporting no expected effect on RNA splicing. Details ▾Hide ▴
Evidence considered
  • Synonymous substitution p.(Thr123=)
  • canonical_splice_consensus=false
  • SpliceAI max delta score 0.00
Sources
spliceai ↗pvs1_variant_assessment

Not met · 4 · evaluated, threshold not reached

PS4 Available evidence does not show enrichment of this variant in affected individuals. Instead, the variant is common in gnomAD, including East Asian frequencies above 1%, which argues against disease-specific case enrichment. Details ▾Hide ▴
Evidence considered
  • gnomAD v2 East Asian AF 1.11791%
  • gnomAD v4 East Asian AF 1.22098%
  • ClinVar predominantly benign/likely benign submissions
Still missing
  • Independent affected proband counts with phenotype confirmation were not identified.
Sources
gnomad_v2 ↗gnomad_v4 ↗clinvar ↗
PM1 No evidence identified this site as a mutational hotspot or a well-established critical functional region without benign variation. Cancer Hotspots did not identify a significant hotspot at this residue. Details ▾Hide ▴
Evidence considered
  • No significant hotspot identified for NF1 T123
Sources
hotspots ↗
PM2 Population frequency is well above rarity thresholds for PM2. In gnomAD, the East Asian allele frequency is 1.11791% in v2.1 and 1.22098% in v4.1, so this variant is not absent or rare in population databases. Details ▾Hide ▴
Evidence considered
  • gnomAD v2 East Asian AF 1.11791%
  • gnomAD v4 East Asian AF 1.22098%
Sources
gnomad_v2 ↗gnomad_v4 ↗
PP3 Available computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00
Sources
spliceai ↗

Not assessed · 13 · no assessment recorded

PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant. Details ▾Hide ▴
Still missing
  • Patient-level parental testing data were not identified.
PS3 No well-established functional study was identified showing a damaging effect of this variant on NF1 function or splicing. Details ▾Hide ▴
Still missing
  • Published RNA or functional assay data for this exact variant were not identified.
PM6 No assumed de novo occurrence without full parentage confirmation was identified for this variant. Details ▾Hide ▴
Still missing
  • Patient-level parental testing details were not identified.
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Still missing
  • Informative family segregation data were not identified.
PP4 No phenotype-specific evidence was identified linking this exact variant to a highly specific NF1 clinical presentation. Details ▾Hide ▴
Still missing
  • Variant-specific phenotype data were not identified.
PP5 PP5 was not used because current interpretation relies on primary evidence rather than external assertions alone. Details ▾Hide ▴

No further detail was recorded.

BA1 The variant is common in population databases, but no explicit NF1 CSPEC population stand-alone benign threshold was available in the reviewed materials for direct BA1 assignment in this pass. Details ▾Hide ▴
Evidence considered
  • gnomAD v2 East Asian AF 1.11791%
  • gnomAD v4 East Asian AF 1.22098%
  • NF1 CSPEC framework artifact was incomplete
Still missing
  • A directly retrievable NF1 CSPEC BA1 threshold was not available in the reviewed materials.
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗final_classification_framework
BS2 Population observations alone were not treated as confirmed observations in well-phenotyped unaffected individuals for BS2 in this pass. Details ▾Hide ▴
Evidence considered
  • Homozygotes reported in gnomAD
Still missing
  • Confirmed unaffected carrier data were not identified.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established functional study was identified showing that this variant has no damaging effect on splicing or NF1 function. Details ▾Hide ▴
Still missing
  • Exact-variant RNA or functional data demonstrating no effect were not identified.
BS4 No non-segregation data were identified for this variant. Details ▾Hide ▴
Still missing
  • Informative family non-segregation data were not identified.
BP2 No phased observation data with another pathogenic variant were identified for this variant. Details ▾Hide ▴
Still missing
  • Phase data were not identified.
BP5 No alternate molecular explanation was identified for any reported phenotype associated with this exact variant. Details ▾Hide ▴
Still missing
  • Variant-specific clinical case data were not identified.
BP6 BP6 was not used because current interpretation relies on primary evidence rather than external assertions alone. Details ▾Hide ▴

No further detail was recorded.

Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AGeneric PVS1 is not applicable because NF1 loss of function is an established disease mechanism, but this variant is a synonymous substitution, is not a canonical +/-1 or 2 splice-site change, and does not fall into a default null-variant PVS1 category. Details ▾Hide ▴
Evidence considered
  • NF1 loss-of-function mechanism supported at the gene level
  • NM_000267.3:c.369C>G is a synonymous variant
  • canonical_splice_consensus=false
Sources
pvs1_gene_contextpvs1_variant_assessment
PS1 N/APS1 was not applicable because this is a synonymous change and no evidence was identified showing that it creates the same amino acid substitution as an established pathogenic variant. Details ▾Hide ▴
Evidence considered
  • Protein consequence is p.(Thr123=) / p.(T123=)
PM3 N/APM3 was not applicable because no recessive observation data were identified for this NF1 variant. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 was not applicable because this variant does not change protein length and is not an in-frame insertion or deletion or stop-loss variant. Details ▾Hide ▴
Evidence considered
  • Synonymous substitution p.(Thr123=)
PM5 N/APM5 was not applicable because this is not a missense change and same-residue missense comparator logic could not be applied. Details ▾Hide ▴
Evidence considered
  • PM5 candidate review found classic same-residue PM5 semantics not applicable
Sources
pm5_candidates
PP2 N/APP2 was not applicable because this is not a missense variant. Details ▾Hide ▴
Evidence considered
  • Synonymous substitution p.(Thr123=)
BP1 N/ABP1 was not applicable because this is not a missense variant. Details ▾Hide ▴
Evidence considered
  • Synonymous substitution p.(Thr123=)
BP3 N/ABP3 was not applicable because this variant is not an in-frame insertion or deletion in a repetitive region. Details ▾Hide ▴
Evidence considered
  • Synonymous substitution p.(Thr123=)
BP4 N/ABP4 was not separately applied because this synonymous variant is more appropriately considered under BP7 for silent changes with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00
Sources
spliceai ↗

Identifiers

Gene
NF1
Transcript
NM_000267.3
Coding (HGVS c.)
NM_000267.3:c.369C>G
Protein (HGVS p.)
NP_000258.1:p.(Thr123=)
GRCh38
chr17:31163266 C>G
GRCh37
chr17:29490284 C>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 v4.1 595 / 1,614,134 alleles AF 0.000369 · 8 homozygotes · FAF 0.0114
gnomAD v2.1 232 / 282,712 alleles AF 0.000821 · 3 homozygotes · FAF 0.0099

By genetic ancestry

gnomAD v4.1

AF 0.00037 · 595 / 1,614,134 alleles · 8 hom · FAF 0.011
East Asian548 / 44,882 0.0127 hom
Remaining individuals26 / 62,508 0.000421 hom
South Asian18 / 91,082 0.0002
Admixed American1 / 60,012 1.7e-05
European (non-Finnish)2 / 1,180,016 1.7e-06
0 alternate alleles recorded in 5 other groups: European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 0.00082 · 232 / 282,712 alleles · 3 hom · FAF 0.0099
East Asian223 / 19,948 0.0113 hom
Remaining individuals5 / 7,212 0.00069
South Asian4 / 30,614 0.00013
0 alternate alleles recorded in 5 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish).

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.000368619; MAF= 0.03686%, 595/1614134 alleles, homozygotes = 8) and has highest observed frequency in the East Asian population (AF= 0.0122098; MAF= 1.22098%, 548/44882 alleles, homozygotes = 7); grpmax FAF= 0.0113641.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000820623; MAF= 0.08206%, 232/282712 alleles, homozygotes = 3) and has highest observed frequency in the East Asian population (AF= 0.0111791; MAF= 1.11791%, 223/19948 alleles, homozygotes = 3); grpmax FAF= 0.00989917.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP7 SupportingThis is a synonymous variant, it is not a canonical splice-site change, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, supporting no expected effect on RNA splicing. Details ▾Hide ▴
Evidence considered
  • Synonymous substitution p.(Thr123=)
  • canonical_splice_consensus=false
  • SpliceAI max delta score 0.00
Sources
spliceai ↗pvs1_variant_assessment
PP3 Available computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00
Sources
spliceai ↗
BP4 N/ABP4 was not separately applied because this synonymous variant is more appropriately considered under BP7 for silent changes with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

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 v4.1 595 / 1,614,134 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= 0.000368619; MAF= 0.03686%, 595/1614134 alleles, homozygotes = 8) and has highest observed frequency in the East Asian population (AF= 0.0122098; MAF= 1.22098%, 548/44882 alleles, homozygotes = 7); grpmax FAF= 0.0113641.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000820623; MAF= 0.08206%, 232/282712 alleles, homozygotes = 3) and has highest observed frequency in the East Asian population (AF= 0.0111791; MAF= 1.11791%, 223/19948 alleles, homozygotes = 3); grpmax FAF= 0.00989917.

ClinVar

This variant has been reported in ClinVar as Benign (13 clinical laboratories) and as Likely benign (4 clinical laboratories). (ClinVarID = 184262)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV62214161, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.