NM_000267.3:c.4686A>G

NF1 · NP_000258.1:p.(Glu1562=) · NM_000267.3

GRCh37: chr17:29592271 A>G · GRCh38: chr17:31265253 A>G

Gene: NF1 Transcript: NM_000267.3

Final call

VUS

BP7

Variant details

Gene

NF1

Transcript

NM_000267.3

Protein

NP_000258.1:p.(Glu1562=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	Not met	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.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	This variant is synonymous and does not create the same amino acid change as a known pathogenic variant. PS1 is not applicable.
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified. Available evidence does not support PS2.
PS3	Not assessed	No well-established functional study demonstrating a damaging effect of this specific variant was identified. Available evidence does not support PS3.
PS4	Not assessed	No case-control enrichment or sufficiently specific case series for this exact variant were identified. Available evidence does not support PS4.
PM1	Not met	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.	hotspots
PM2	Not met	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.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is intended for recessive disorders with trans observations. NF1 is evaluated here in an autosomal dominant disease context, so PM3 is not applicable.	cspec
PM4	N/A	This variant is not a protein length-changing in-frame deletion, insertion, or stop-loss variant. PM4 is not applicable.
PM5	N/A	This 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.
PM6	Not assessed	No assumed de novo occurrence data for this exact variant were identified. Available evidence does not support PM6.
PP1	Not assessed	No segregation data were identified for this variant. Available evidence does not support PP1.
PP2	N/A	PP2 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.
PP3	Not met	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.	spliceai
PP4	Not assessed	No phenotype or family-history data specific enough to support PP4 were identified. Available evidence does not support PP4.
PP5	N/A	PP5 was not used. Existing database classifications alone were not treated as independent pathogenic evidence for this adjudication.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not assessed	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.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study demonstrating no damaging effect of this specific variant was identified. Available evidence does not support BS3.
BS4	Not assessed	No segregation studies showing lack of segregation with disease were identified. Available evidence does not support BS4.
BP1	N/A	BP1 applies to certain missense variants in genes where truncating variants are the predominant mechanism. This variant is not missense, so BP1 is not applicable.
BP2	Not assessed	No phase data or observations with another pathogenic variant were identified. Available evidence does not support BP2.
BP3	N/A	BP3 applies to in-frame variants in repetitive regions without known function. This variant is a synonymous substitution, so BP3 is not applicable.
BP4	N/A	For this synonymous variant, benign computational evidence is better captured under BP7 rather than BP4. BP4 was not applied separately.	spliceai
BP5	Not assessed	No evidence was identified showing that the observed phenotype is fully explained by an alternate molecular diagnosis. Available evidence does not support BP5.
BP6	N/A	BP6 was not used. Existing ClinVar assertions were considered supportive context only and were not treated as independent benign evidence in this adjudication.	clinvar
BP7	Met	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.	spliceai

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.