NM_000267.3:c.2355A>G

NF1 · NP_000258.1:p.(Glu785=) · NM_000267.3

GRCh37: chr17:29554570 A>G · GRCh38: chr17:31227552 A>G

Gene: NF1 Transcript: NM_000267.3

Final call

VUS

BP7 supporting

Variant details

Gene

NF1

Transcript

NM_000267.3

Protein

NP_000258.1:p.(Glu785=)

gnomAD AF

2.354682037370043e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000267.3:c.2355A>G (p.Glu785=) is a synonymous variant in NF1 with no predicted splice impact (SpliceAI max delta 0.00).

The variant is present in gnomAD v2.1 at a frequency of 0.00141% (4/282,792 alleles) and in gnomAD v4.1 at 0.00235% (38/1,613,806 alleles), with no homozygotes observed.

ClinVar classifies this variant as Likely benign (Variation ID 230539) based on submissions from 5 clinical laboratories, with a review status of criteria provided, single submitter (1-star).

No publications directly mention or provide variant-specific evidence for NM_000267.3:c.2355A>G; literature review of available full-text articles (PMID: 25741868, 17636453, 25394175, 26324357) confirmed this variant is not cited in any publication.

BP7 is met at supporting strength: this synonymous variant is predicted to have no splice impact by SpliceAI and is present in population databases, consistent with a non-conserved, likely benign nucleotide position.

No pathogenic criteria are met. No benign criteria beyond BP7 are met. The ClinVar Likely benign classification is consistent with the evidence that this synonymous variant lacks functional consequence.

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	N/A	NM_000267.3:c.2355A>G is a synonymous variant (p.Glu785=) that does not result in a null allele (nonsense, frameshift, or canonical splice disruption). PVS1 is not applicable to synonymous variants.	pvs1_variant_assessment
PS1	N/A	PS1 applies when a different nucleotide change at the same position results in the same amino acid change as a known pathogenic variant. This is a synonymous variant with no amino acid change (p.Glu785=). PS1 is not applicable.
PS2	Not met	No de novo observations have been reported for NM_000267.3:c.2355A>G. No publications mention this specific variant.	clinvar
PS3	Not met	No functional studies have been performed on NM_000267.3:c.2355A>G (p.Glu785=). This synonymous variant has no predicted splice impact (SpliceAI delta 0.00), and no experimental functional data exist in the literature.	spliceai
PS4	Not met	No case-control studies demonstrate enrichment of NM_000267.3:c.2355A>G in affected individuals. The variant has been observed in gnomAD in 4 (v2.1) to 38 (v4.1) alleles, inconsistent with a highly penetrant pathogenic variant. ClinVar lists the variant as Likely benign by 5 clinical laboratories, with no reports of the variant in affected individuals with NF1-specific phenotype.	gnomad_v2 gnomad_v4 clinvar
PS5	N/A	PS5 applies when a different pathogenic missense change has been observed at the same amino acid residue. NM_000267.3:c.2355A>G is a synonymous variant (p.Glu785=) with no missense change. PS5 is not applicable.
PM1	Not met	Although residue Glu785 falls within the cysteine-serine rich domain (CSD, residues ~543-909) of neurofibromin, this is a synonymous variant (p.Glu785=) with no predicted splice impact (SpliceAI delta 0.00). The amino acid sequence is unchanged, and the nucleotide substitution does not alter protein structure or function. Location in a functional domain does not confer pathogenic significance when the protein product is unaltered. Residue 785 is not a statistically significant hotspot (cancerhotspots.org).	spliceai
PM2	Not met	NM_000267.3:c.2355A>G is present in gnomAD v2.1 (4/282,792 alleles; AF 0.00141%) and gnomAD v4.1 (38/1,613,806 alleles; AF 0.00235%). Although the allele frequency is below the 0.1% threshold for dominant disorders, this is a synonymous variant with no predicted splice impact (SpliceAI delta 0.00). Population presence at any frequency in a synonymous variant without functional consequence does not support pathogenicity; rather, it is consistent with a benign polymorphism. PM2 is not appropriately applied to synonymous variants lacking functional evidence.	gnomad_v2 gnomad_v4 spliceai
PM3	N/A	Skipped per case instructions. PM3 applies to variants observed in trans with a pathogenic variant for recessive disorders; NF1 is autosomal dominant.
PM4	N/A	Skipped per case instructions. PM4 applies to in-frame deletions/insertions or stop-loss variants; NM_000267.3:c.2355A>G is a single-nucleotide synonymous substitution.
PM5	N/A	NM_000267.3:c.2355A>G is a synonymous variant (p.Glu785=). PM5 applies to missense variants at the same residue as a known pathogenic missense change. No amino acid change occurs; PM5 is not applicable.	pm5_candidates
PM6	Not met	No de novo observations have been reported for NM_000267.3:c.2355A>G. No publications mention this variant in the context of assumed de novo status.	clinvar
PP1	Not met	No segregation data are available for NM_000267.3:c.2355A>G. No publications report cosegregation of this variant with NF1 in affected families.	clinvar
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. NM_000267.3:c.2355A>G is a synonymous variant, not a missense change. PP2 is not applicable.
PP3	Not met	In silico prediction tools do not support a deleterious effect for this synonymous variant. REVEL and BayesDel scores are not available for synonymous variants. SpliceAI predicts no splice impact (max delta 0.00). No computational evidence supports pathogenicity.	spliceai
PP4	Not met	No patient phenotype or family history data are available for this case. PP4 requires that the patient's phenotype is highly specific for NF1, which cannot be assessed without clinical information.
PP5	Not met	ClinVar classifies NM_000267.3:c.2355A>G as Likely benign (Variation ID 230539, 5 clinical laboratories, review status: criteria provided, single submitter). PP5 requires a reputable source to report the variant as pathogenic; this variant is reported as benign/likely benign. PP5 is not met.	clinvar
BA1	Not met	The maximum allele frequency of NM_000267.3:c.2355A>G in gnomAD is 0.00310% (gnomAD v2.1 NFE) and 0.00320% (gnomAD v4.1). This is well below the BA1 threshold of >1%. BA1 is not met.	gnomad_v2 gnomad_v4
BS1	Not met	The maximum allele frequency of NM_000267.3:c.2355A>G in gnomAD is 0.00310% (gnomAD v2.1 NFE) and 0.00320% (gnomAD v4.1). This is well below the BS1 threshold of >0.3% for dominant disorders. BS1 is not met.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygotes are observed in gnomAD (0 homozygotes in both v2.1 and v4.1). No evidence exists of this variant being observed in a healthy adult individual in the absence of NF1. BS2 requires observation in a healthy adult without the disease, which is not documented here.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies demonstrate that NM_000267.3:c.2355A>G has no damaging effect on protein function or splicing. While SpliceAI predicts no splice impact (delta 0.00), BS3 requires well-established functional studies showing no deleterious effect, which are not available.	spliceai
BS4	Not met	No segregation data are available to demonstrate lack of cosegregation of NM_000267.3:c.2355A>G with NF1. BS4 requires observation of non-segregation with disease in affected family members.	clinvar
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. NM_000267.3:c.2355A>G is a synonymous variant, not missense. BP1 is not applicable.
BP2	Not met	No observation of NM_000267.3:c.2355A>G in trans with a known pathogenic NF1 variant has been reported. BP2 requires documentation of the variant occurring in trans with a pathogenic variant without clinical features of the disorder.	gnomad_v2 gnomad_v4
BP3	N/A	Skipped per case instructions. BP3 applies to in-frame deletions/insertions in repetitive regions; not applicable to a single-nucleotide synonymous substitution.
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. Only SpliceAI is available for this synonymous variant (delta 0.00). REVEL and BayesDel are not applicable to synonymous variants. A single line of computational evidence is insufficient to meet BP4.	spliceai
BP5	Not met	No observation of NM_000267.3:c.2355A>G in a case where an alternate molecular basis for disease has been identified. BP5 requires documentation of the variant occurring in an individual with a different confirmed genetic etiology for NF1.	clinvar
BP6	Not met	ClinVar classifies NM_000267.3:c.2355A>G as Likely benign (Variation ID 230539) with a review status of 'criteria provided, single submitter' (1-star). BP6 requires a reputable source to report the variant as benign with evidence unavailable for independent evaluation. While 5 clinical laboratories have submitted Likely benign classifications, the 1-star review status falls short of the 3-star expert panel threshold typically required for BP6 application under both VCEP and generic ACMG/AMP frameworks.	clinvar
BP7	Met	NM_000267.3:c.2355A>G is a synonymous (silent) variant (p.Glu785=). SpliceAI predicts no impact on splicing with a maximum delta score of 0.00, indicating no effect on splice consensus sequences and no creation of a novel splice site. The variant is present in gnomAD in 38 alleles (v4.1), suggesting the nucleotide position is not highly conserved across the population. BP7 is met at supporting strength.	spliceai gnomad_v2 gnomad_v4

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