Variant classification summary

NM_000760.4:c.1853C>T

CSF3R · NP_000751.1:p.(Thr618Ile) · NM_000760.4

GRCh37: chr1:36933434 G>A · GRCh38: chr1:36467833 G>A

Gene: CSF3R Transcript: NM_000760.4

Final call

Likely Pathogenic

PS4 strong PS3 moderate PM2 supporting BP4 supporting

Variant details

Gene

CSF3R

Transcript

NM_000760.4

Protein

NP_000751.1:p.(Thr618Ile)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PS4 strong is supported by 10/12 CNL cases versus 0/170 controls.

2

Likely Pathogenic: PS3 moderate is supported by variant-specific mouse and cellular functional assays.

3

Likely Pathogenic: PM2 supporting is supported by absence from queried gnomAD datasets.

4

Likely Pathogenic: BP4 supporting reflects REVEL 0.143 but does not independently satisfy a benign rule.

Final determination: Under the generic ACMG/AMP 2015 fallback, one Strong pathogenic criterion plus one Moderate pathogenic criterion supports Likely Pathogenic; BP4 Supporting alone does not satisfy a benign rule.

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: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: the evidence confirms CSF3R Thr618Ile but provides no pathogenic alternate nucleotide change producing the same amino-acid substitution.	PMID:23604229
PS2	Not assessed	Not assessed: germline origin is reported, but confirmed maternity and paternity, disease phenotype, and absence of family history are undocumented.	clinvar
PS3	Met	Met, moderate: variant-specific mouse transplantation and colony assays show cytokine-independent growth, granulocytic expansion, and lethal myeloproliferative disease.	PMID:24081659 PMID:31784538
PS4	Met	Met: CSF3R T618I occurred in 10/12 CNL cases versus 0/170 comparison controls, yielding continuity-corrected OR 1,432.2 (95% CI 64.5–31,782.9), above 5 with CI excluding 1.	PMID:23604229
PM1	Not met	Not met: CSF3R T618 had no statistically significant hotspot, and no critical domain without benign variation was documented.	hotspots cosmic
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1, v4.1, and non-cancer subsets, meeting the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: CSF3R T618I is associated with dominant hereditary neutrophilia or somatic myeloid neoplasia, not an established recessive disorder.	clinvar
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different missense change at CSF3R residue Thr618 was established as pathogenic in the available evidence.	PMID:23604229
PM6	Not assessed	Not assessed: germline origin is reported, but an assumed de novo event and the parental-testing status are not documented.	clinvar
PP1	Not assessed	Not assessed: a vague segregation statement lacks the affected-relative count, genotypes, phenotypes, and meioses needed to establish PP1.	clinvar
PP2	Not assessed	Not assessed: CSF3R missense disease mechanism is documented, but no gene-level low benign-missense-rate measure was provided.	PMID:23604229 gnomad_v2 gnomad_v4
PP3	Not met	Not met: missense REVEL score 0.143 is below the >=0.644 PP3 supporting threshold.	revel
PP4	Not assessed	Not assessed: the patient's phenotype and family history are unavailable, so specificity for a disease with a single genetic etiology cannot be evaluated.
PP5	Not met	Not met: ClinVar has Pathogenic/Likely pathogenic laboratory submissions but zero expert-panel submissions, so the required expert-panel classification is absent.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1, v4.1, and non-cancer subsets, far below the >=0.05 BA1 frequency threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from all queried gnomAD datasets, so no filtering allele frequency reaches the generic >=0.01 BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no documented healthy adult homozygote, heterozygote, or hemizygote observation satisfies the BS2 requirement.
BS3	Not assessed	Not assessed: no variant-specific assay demonstrates absence of damaging effect on CSF3R function or splicing.
BS4	Not assessed	Not assessed: no affected-family-member genotype and phenotype data demonstrate lack of segregation with disease.	clinvar
BP1	Not met	Not met: CSF3R disease includes recurrent activating missense mutations, including T618I, rather than being primarily truncating.	PMID:23604229
BP2	Not assessed	Not assessed: no documented pathogenic partner variant or phase result establishes the required cis or trans relationship for BP2.	clinvar PMID:23604229
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met, supporting: missense REVEL score 0.143 is below the <=0.29 BP4 supporting threshold.	revel
BP5	Not assessed	Not assessed: no human case-level evidence shows this variant with an alternate molecular basis for disease; experimental mouse co-mutation data are insufficient.	PMID:31784538
BP6	Not met	Not met: ClinVar has no exact-variant benign or likely benign expert-panel classification and instead contains only non-expert pathogenic submissions.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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.