Variant classification summary

NM_001042492.2:c.2022C>T

NF1 · NP_001035957.1:p.(Ser674=) · NM_001042492.2

GRCh37: chr17:29553473 C>T · GRCh38: chr17:31226455 C>T

Gene: NF1 Transcript: NM_001042492.2

Final call

Benign

BA1 stand-alone benign BS1 supporting BS2 supporting BP7 supporting

Variant details

Gene

NF1

Transcript

NM_001042492.2

Protein

NP_001035957.1:p.(Ser674=)

gnomAD AF

0.0016473035166025636 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BA1 (stand-alone benign): highest population allele frequency 3.06% (African ancestry, gnomAD v4.1) exceeds the >1% threshold about 3-fold.

2

BS1 (supporting): observed allele frequency exceeds that expected for a dominant NF1 allele by more than 150-fold.

3

BS2 (supporting): 44 homozygotes in general-population cohorts are incompatible with a near-fully penetrant dominant disease allele.

4

BP7 (supporting): synonymous change with no predicted splice impact (SpliceAI max delta 0.009) at a position with high population frequency.

5

Synthesis: Benign — BA1 at stand-alone strength alone is sufficient under the generic combination rules, with BS1, BS2, and BP7 concordant and no pathogenic criterion met.

Final determination: Generic ACMG/AMP 2015 combination rule: BA1 (stand-alone benign) alone is sufficient for a Benign classification; here it is reinforced by two supporting benign criteria (BS1 + BS2) and BP7 (supporting), with no pathogenic criteria met.

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	Not applicable: this synonymous change leaves the protein unchanged, so no loss-of-function mechanism such as nonsense-mediated decay is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: the synonymous change produces no altered amino acid to compare with previously established pathogenic variants.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no confirmed de novo occurrence with verified parentage is reported for this variant.	cspec PMID:25741868
PS3	Not met	Not met: no functional study of this variant exists — no assay of neurofibromin activity, splicing, or RAS pathway function was found.	cspec generic_acmg_combination_rules PMID:25741868
PS4	Not met	Not met: no case-control or NF1 case-cohort study shows enrichment; ClinVar carries only routine laboratory Benign classifications.	clinvar gnomad_v2 gnomad_v4 cspec PMID:25741868
PM1	N/A	Not applicable: no altered residue exists to evaluate for a mutational hotspot or critical functional domain.	generic_acmg_combination_rules
PM2	Not met	Not met: present at 0.16% overall and 3.06% in African ancestry in gnomAD, far above the <0.1% rarity threshold.	gnomad_v4 gnomad_v2 gnomad_canada PMID:25741868 cspec
PM3	N/A	Not applicable: NF1 is autosomal dominant, so the recessive-disorder premise of PM3 does not apply.	cspec PMID:25741868
PM4	N/A	Not applicable: the synonymous change causes no protein length alteration for this criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change occurs, so there is nothing to compare with pathogenic missense at this residue.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no assumed de novo occurrence is reported for this variant in any source.	cspec PMID:25741868
PP1	Not assessed	Not assessed: no segregation data in affected family members were available.	cspec PMID:25741868
PP2	N/A	Not applicable: this missense-only criterion does not apply to a synonymous variant.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.009 is far below the 0.2 cutoff for predicted splice impact.	spliceai generic_acmg_combination_rules
PP4	Not met	Not met: no proband with a documented NF1 phenotype carrying this exact variant is reported.	clinvar cspec PMID:25741868
PP5	Not met	Not met: no ClinVar expert panel has classified this variant as pathogenic (zero expert-panel submissions).	clinvar cspec PMID:25741868
BA1	Met	Met (stand-alone benign): highest population allele frequency 3.06% (African ancestry, gnomAD v4.1) exceeds the >1% BA1 threshold about 3-fold.	gnomad_v4 gnomad_v2 gnomad_canada PMID:25741868 cspec
BS1	Met	Met (supporting): observed maximum allele frequency 3.06% exceeds the ~0.01–0.02% expected for a dominant NF1 allele by over 150-fold.	gnomad_v4 gnomad_v2 gnomad_canada PMID:25741868 cspec
BS2	Met	Met (supporting): 44 homozygotes in gnomAD v4.1 general-population cohorts are incompatible with a near-fully penetrant dominant NF1 allele.	gnomad_v4 gnomad_v2 PMID:25741868 cspec
BS3	Not met	Not met: no well-established functional study demonstrates absence of damaging effect; the SpliceAI prediction is in silico only.	cspec generic_acmg_combination_rules PMID:25741868 spliceai
BS4	Not assessed	Not assessed: no family testing data exist to establish lack of segregation in affected relatives.	cspec PMID:25741868
BP1	N/A	Not applicable: this criterion concerns missense variants, and the change is synonymous.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no allelic-phase or co-occurrence data with a pathogenic variant are reported.	clinvar cspec PMID:25741868 gnomad_v4
BP3	N/A	Not applicable: no in-frame indel in a repetitive region is involved.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: the only computational no-impact line (SpliceAI) is already counted under BP7 and cannot be double-counted here.	spliceai generic_acmg_combination_rules
BP5	Not met	Not met: no proband-level evidence of an alternate genetic cause of disease is reported.	clinvar cspec PMID:25741868
BP6	Not met	Not met: no expert panel has classified this variant as benign; routine laboratory consensus does not trigger BP6.	clinvar cspec PMID:25741868
BP7	Met	Met (supporting): synonymous change, no predicted splice impact (SpliceAI max delta 0.009), and high population frequency indicating no strong conservation.	spliceai generic_acmg_combination_rules gnomad_v4 gnomad_v2 gnomad_canada

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