Variant classification summary

NM_000267.3:c.846G>A

NF1 · NP_000258.1:p.(Gln282=) · NM_000267.3

GRCh37: chr17:29509641 G>A · GRCh38: chr17:31182623 G>A

Gene: NF1 Transcript: NM_000267.3

Final call

Benign

BA1 stand-alone benign BS1 strong benign BS2 strong benign BP4 supporting benign BP6 supporting benign BP7 supporting benign

Variant details

Gene

NF1

Transcript

NM_000267.3

Protein

NP_000258.1:p.(Gln282=)

gnomAD AF

0.0036570615615690045 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BA1 is met: allele frequency of 3.24% in the South Asian subpopulation (gnomAD v2.1) with 27 homozygotes and grpmax FAF of 3.07% far exceeds the 1% stand-alone benign threshold, establishing NM_000267.3:c.846G>A as a common population polymorphism incompatible with NF1 pathogenicity.

2

BS1 is met: overall gnomAD allele frequency of 0.496% (v2.1, 1400/282340 alleles) exceeds the 0.3% strong benign threshold.

3

BS2 is met: the variant is observed in 29 homozygous individuals in gnomAD v2.1 and 90 homozygous individuals in gnomAD v4.1, which is incompatible with a highly penetrant autosomal dominant disorder like NF1.

4

This variant has been reported in ClinVar as Benign by 14 clinical laboratories and as Likely benign by 9 clinical laboratories, supporting BP6.

5

SpliceAI predicts no significant splicing impact (max delta 0.06) and the variant is synonymous (p.Q282=) with no amino acid change, supporting BP4 and BP7.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong 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	PVS1 is reserved for null variants (nonsense, frameshift, canonical splice sites, initiation codon, exon deletions). NM_000267.3:c.846G>A is a synonymous variant (p.Q282=) with no predicted effect on splicing (SpliceAI max delta 0.06). It does not fall into any PVS1 null-variant bucket.	pvs1_variant_assessment spliceai
PS1	N/A	PS1 requires a different nucleotide change at the same position resulting in the same amino acid change that has been previously established as pathogenic. This is a synonymous variant with no amino acid change; PS1 is not applicable.
PS2	Not assessed	No de novo observation data available for this variant in any reviewed source. Without a specific de novo report, PS2 cannot be assessed.
PS3	Not assessed	No functional studies were identified for this variant in any reviewed publication or database. Variant-specific functional evidence is absent.
PS4	Not met	PS4 requires enrichment in affected individuals versus controls. This variant has a gnomAD overall allele frequency of 0.496% (v2.1) and 0.366% (v4.1) with 29 and 90 homozygotes respectively, which is incompatible with a pathogenic role in a highly penetrant autosomal dominant disorder like NF1.	gnomad_v2 gnomad_v4
PS5	Not met	PS5 requires a reputable source to have reported the variant as pathogenic. All ClinVar submissions classify this variant as Benign (14 clinical laboratories) or Likely benign (9 clinical laboratories). No laboratory or reputable source has reported it as pathogenic.	clinvar
PM1	N/A	PM1 applies to missense variants located in a mutational hotspot or critical functional domain without benign variation. This is a synonymous variant with no amino acid change; PM1 is not applicable. Additionally, the variant is not located in a statistically significant hotspot.
PM2	Not met	PM2 requires absence or very low frequency (<0.1%) in population databases. This variant is present in gnomAD v2.1 at 0.496% (1400/282340 alleles) and v4.1 at 0.366% (5902/1613864 alleles), far exceeding the 0.1% threshold. PM2 is not met.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 requires a different pathogenic amino acid change at the same residue. This is a synonymous variant with no amino acid change. Protein consequence is p.Q282= (no change). The PM5 candidate harvest was unable to confirm classic same-residue semantics.	pm5_candidates
PM6	N/A	PM6 requires a de novo observation without confirmation of paternity and maternity. No de novo data are available for this variant in any reviewed source. This criterion is not applicable.
PP1	Not assessed	No segregation data are available for this variant in any reviewed publication or database. PP1 cannot be assessed without family-level cosegregation evidence.
PP2	N/A	PP2 applies to missense variants in genes where missense variants are a common disease mechanism and the gene has a low rate of benign missense variation. This is a synonymous variant, not a missense variant. Not applicable.
PP3	Not met	PP3 requires multiple lines of computational evidence supporting a deleterious effect. SpliceAI predicts no significant splicing impact (max delta 0.06). REVEL and BayesDel scores are not available (not applicable to synonymous variants). No in silico evidence supports a deleterious effect.	spliceai
PP4	N/A	PP4 requires the variant to be identified in an individual with a phenotype highly specific for the disease. No individual phenotype data are available for this variant. Not applicable without case-level clinical information.
PP5	Not met	PP5 requires a reputable source to have recently reported the variant as pathogenic. All ClinVar submissions classify this variant as Benign (14 labs) or Likely benign (9 labs). The ClinGen NF1 CSPEC exists (v1.0.0) but provides no variant-specific classification. No reputable source classifies this variant as pathogenic.	clinvar cspec
BA1	Met	The allele frequency in the South Asian subpopulation is 3.24% (gnomAD v2.1) and 3.27% (gnomAD v4.1) with 27 and 85 homozygotes respectively. The gnomAD grpmax filtering allele frequency is 3.07% (v2.1) and 3.17% (v4.1). These frequencies far exceed the 1% threshold for BA1, establishing this variant as a common population polymorphism incompatible with NF1 pathogenicity.	gnomad_v2 gnomad_v4
BS1	Met	The overall allele frequency is 0.496% (gnomAD v2.1, 1400/282340 alleles) and 0.366% (gnomAD v4.1, 5902/1613864 alleles). This exceeds the 0.3% threshold for BS1, indicating the variant is more common than expected for a pathogenic NF1 variant.	gnomad_v2 gnomad_v4
BS2	Met	The variant has been observed in the homozygous state in 29 individuals in gnomAD v2.1 and 90 individuals in gnomAD v4.1. Homozygosity for a variant in NF1, a gene associated with a highly penetrant autosomal dominant disorder, is incompatible with a pathogenic role.	gnomad_v2 gnomad_v4
BS3	Not assessed	No functional studies have been identified for this variant in any reviewed publication or database. BS3 cannot be assessed without variant-specific functional evidence demonstrating no damaging effect.
BS4	Not assessed	BS4 requires documented lack of cosegregation with disease in affected family members. While the high population frequency and homozygosity strongly suggest lack of segregation with NF1, formal family-based segregation studies are not available for this variant.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary known disease mechanism. This is a synonymous variant with no amino acid change; BP1 is not applicable.
BP2	N/A	BP2 applies to a variant observed in trans with a pathogenic variant in a fully penetrant dominant disorder. Given the variant's high population frequency (0.5%), the probability of coincidental co-occurrence with a pathogenic NF1 variant is substantial; BP2 is not applicable.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. SpliceAI predicts no significant splicing impact (max delta 0.06). The variant is synonymous (p.Q282=) with no amino acid change and no predicted effect on splicing. No in silico tools predict a deleterious effect.	spliceai
BP5	N/A	BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No case-specific data are available for this variant. Not applicable.
BP6	Met	A reputable source classifies this variant as benign. ClinVar reports 14 clinical laboratories classifying this variant as Benign and 9 as Likely benign (ClinVar variation ID 184123). The consensus across multiple independent clinical laboratories supports a benign interpretation.	clinvar
BP7	Met	This is a synonymous variant (p.Q282=) at a nucleotide position with no predicted impact on splicing (SpliceAI max delta 0.06). The variant does not alter the primary amino acid sequence and has no predicted effect on mRNA splicing, consistent with BP7 criteria for a benign synonymous variant.	spliceai

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