Classification rationale

BS1BP7 Likely Benign

NF1 c.369C>G

The NF1 c.369C>G (p.Thr123=) variant has been reported in ClinVar, where benign and likely benign classifications predominate.¹ 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.² 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 PP3.³

BS1 + BP7 → Likely Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗

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.

Gene diagram · NM_000267.3 · variants mapped to exon structure

NF1 NM_000267.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 17 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

BS1 strong review Benign

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.

gnomAD v2 East Asian AF 1.11791%gnomAD v4 East Asian AF 1.22098%Multiple homozygotes observed in gnomAD

gnomad_v2 ↗gnomad_v4 ↗

BP7 supporting review Benign

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.

Synonymous substitution p.(Thr123=)canonical_splice_consensus=falseSpliceAI max delta score 0.00

spliceai ↗

Assessed · not applied · 4 not met · 13 not assessed

Pathogenic

PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant.

PS3 No well-established functional study was identified showing a damaging effect of this variant on NF1 function or splicing.

PS4 Available evidence does not show enrichment of this variant in affected individuals.

PM1 No evidence identified this site as a mutational hotspot or a well-established critical functional region without benign variation.

PM2 Population frequency is well above rarity thresholds for PM2.

PM6 No assumed de novo occurrence without full parentage confirmation was identified for this variant.

PP1 No segregation data were identified for this variant.

PP3 Available computational evidence does not support a deleterious effect.

PP4 No phenotype-specific evidence was identified linking this exact variant to a highly specific NF1 clinical presentation.

PP5 PP5 was not used because current interpretation relies on primary evidence rather than external assertions alone.

Benign

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.

BS2 Population observations alone were not treated as confirmed observations in well-phenotyped unaffected individuals for BS2 in this pass.

BS3 No well-established functional study was identified showing that this variant has no damaging effect on splicing or NF1 function.

BS4 No non-segregation data were identified for this variant.

BP2 No phased observation data with another pathogenic variant were identified for this variant.

BP5 No alternate molecular explanation was identified for any reported phenotype associated with this exact variant.

BP6 BP6 was not used because current interpretation relies on primary evidence rather than external assertions alone.

N/A · 9 PVS1 · PS1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3 · BP4

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

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.

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.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.037% · 595 / 1,614,134
8 hom · FAF 1.1%

East Asian 548 / 44,882	1.2% 7 hom
Remaining individuals 26 / 62,508	0.042% 1 hom
South Asian 18 / 91,082	0.02%
Admixed American 1 / 60,012	0.0017%
European (non-Finnish) 2 / 1,180,016	0.00017%

+ 5 not observed (European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.082% · 232 / 282,712
3 hom · FAF 0.99%

East Asian 223 / 19,948	1.1% 3 hom
Remaining individuals 5 / 7,212	0.069%
South Asian 4 / 30,614	0.013%

+ 5 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish))

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

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

ClinVar ↗

In silico

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

SpliceAI ↗

Functional Unknown Oncogenic Effect

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

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

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

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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