NM_000267.3:c.369C>G

NF1 · NP_000258.1:p.(Thr123=) · NM_000267.3

GRCh37: chr17:29490284 C>G · GRCh38: chr17:31163266 C>G

Gene: NF1 Transcript: NM_000267.3

Final call

Likely Benign

BS1 strong benign BP7 supporting benign

Variant details

Gene

NF1

Transcript

NM_000267.3

Protein

NP_000258.1:p.(Thr123=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Generic 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.	pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 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.
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified for this variant.
PS3	Not assessed	No well-established functional study was identified showing a damaging effect of this variant on NF1 function or splicing.
PS4	Not met	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.	gnomad_v2 gnomad_v4 clinvar
PM1	Not met	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.	hotspots
PM2	Not met	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.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 was not applicable because no recessive observation data were identified for this NF1 variant.
PM4	N/A	PM4 was not applicable because this variant does not change protein length and is not an in-frame insertion or deletion or stop-loss variant.
PM5	N/A	PM5 was not applicable because this is not a missense change and same-residue missense comparator logic could not be applied.	pm5_candidates
PM6	Not assessed	No assumed de novo occurrence without full parentage confirmation was identified for this variant.
PP1	Not assessed	No segregation data were identified for this variant.
PP2	N/A	PP2 was not applicable because this is not a missense variant.
PP3	Not met	Available computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.	spliceai
PP4	Not assessed	No phenotype-specific evidence was identified linking this exact variant to a highly specific NF1 clinical presentation.
PP5	Not assessed	PP5 was not used because current interpretation relies on primary evidence rather than external assertions alone.
BA1	Not assessed	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.	gnomad_v2 gnomad_v4 cspec final_classification_framework
BS1	Met	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 gnomad_v4
BS2	Not assessed	Population observations alone were not treated as confirmed observations in well-phenotyped unaffected individuals for BS2 in this pass.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study was identified showing that this variant has no damaging effect on splicing or NF1 function.
BS4	Not assessed	No non-segregation data were identified for this variant.
BP1	N/A	BP1 was not applicable because this is not a missense variant.
BP2	Not assessed	No phased observation data with another pathogenic variant were identified for this variant.
BP3	N/A	BP3 was not applicable because this variant is not an in-frame insertion or deletion in a repetitive region.
BP4	N/A	BP4 was not separately applied because this synonymous variant is more appropriately considered under BP7 for silent changes with no predicted splice impact.	spliceai
BP5	Not assessed	No alternate molecular explanation was identified for any reported phenotype associated with this exact variant.
BP6	Not assessed	BP6 was not used because current interpretation relies on primary evidence rather than external assertions alone.
BP7	Met	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.	spliceai pvs1_variant_assessment

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.