Variant classification summary

NM_000492.4:c.3909C>G

CFTR · NP_000483.3:p.(Asn1303Lys) · NM_000492.4

GRCh37: chr7:117292931 C>G · GRCh38: chr7:117652877 C>G

Gene: CFTR Transcript: NM_000492.4

Final call

Likely Pathogenic

PS3 strong PM1 moderate PP3 moderate PP5 supporting

Variant details

Gene

CFTR

Transcript

NM_000492.4

Protein

NP_000483.3:p.(Asn1303Lys)

gnomAD AF

0.0001576912005807041 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PS3 strong from near-absent N1303K-CFTR maturation and chloride transport.

2

Likely Pathogenic: PM1 moderate from the variant's location in CFTR NBD2 with severe functional impairment.

3

Likely Pathogenic: PP3 moderate because REVEL 0.83 exceeds the calibrated threshold of 0.773.

4

Likely Pathogenic: PP5 supporting because the exact-variant CFTR2 expert panel classified it as Pathogenic.

Final determination: Under the generic ACMG/AMP 2015 fallback, 1 Strong plus 1–2 Moderate pathogenic criteria supports Likely Pathogenic; PS3 strong with PM1 and PP3 moderate satisfies this 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: p.Asn1303Lys is pathogenic, but no distinct pathogenic nucleotide change producing the same amino-acid substitution was documented.	clinvar
PS2	Not assessed	Not assessed: parental maternity and paternity confirmation, de novo status, and absence of family history are not documented.
PS3	Met	Met, strong: N1303K mature CFTR was 0.5% of normal and baseline chloride transport was 0.0% of normal in a controlled variant-specific assay.	PMID:23891399
PS4	Not assessed	Not assessed: the N1303K report lacks complete case and control denominators, so OR and 95% CI cannot be calculated against the >5.0 and non-1.0 criteria.	PMID:1998343
PM1	Met	Met: p.Asn1303Lys lies in CFTR NBD2, where mature CFTR was 0.5% and baseline chloride transport 0.0% of normal.	PMID:23891399 gnomad_v4 cosmic hotspots
PM2	Not met	Not met: the lowest reported filtering grpmax FAF is 0.00012449, exceeding the generic PM2 threshold of 0.0001, and the variant is present in both datasets.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no parental or offspring phasing documents c.3909C>G in trans with a named pathogenic CFTR variant.	PMID:1998343 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 pathogenic missense substitution at CFTR residue Asn1303 was documented in the supplied comparator evidence.	pm5_candidates
PM6	Not assessed	Not assessed: no evidence documents an assumed de novo occurrence with unconfirmed maternity and paternity.
PP1	Not assessed	Not assessed: no documented co-segregation data from multiple affected family members or informative meioses are available.
PP2	Not assessed	Not assessed: gene-level evidence for both low benign missense variation and a common missense disease mechanism is unavailable.	clinvar gnomad_v4
PP3	Met	Met at moderate strength: missense REVEL score 0.83 meets the supplied PP3 threshold of >=0.773.	revel
PP4	Not assessed	Not assessed: no case-specific phenotype or family-history details establish a highly specific single-etiology presentation.
PP5	Met	Met at supporting strength: ClinVar's exact-variant CFTR2 expert panel classification is Pathogenic, satisfying the qualifying PP5 source requirement.	clinvar PMID:1998343
BA1	Not met	Not met: gnomAD grpmax FAF is 0.00015542 at most, below the generic BA1 threshold of 0.05, with higher subgroup point estimates lacking 2000 observed alleles.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the maximum gnomAD grpmax FAF is 0.00015542, far below the generic BS1 threshold of 0.01, and small-subgroup point estimates are not admissible.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: no homozygotes were observed in gnomAD v2.1 or v4.1, which report 0 homozygotes across 280898 and 1598060 alleles, respectively.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: N1303K showed 0.5% mature CFTR and 0.0% baseline chloride transport, indicating damage rather than preserved protein function.	PMID:23891399
BS4	Not assessed	Not assessed: no affected relatives lacking the variant or other documented family non-segregation evidence is available.
BP1	Not assessed	Not assessed: gene-wide evidence showing that CFTR disease-causing variants are primarily truncating is unavailable.	clinvar
BP2	Not assessed	Not assessed: no individual-level phase result shows c.3909C>G in trans or cis with another pathogenic variant.	PMID:1998343 clinvar
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	Not met	Not met: missense REVEL score 0.83 exceeds the BP4 supporting threshold of <=0.29.	revel
BP5	Not assessed	Not assessed: no documented alternate molecular basis explains the disease in the case carrying this variant.
BP6	Not met	Not met: the exact-variant ClinVar expert panel classifies N1303K as Pathogenic, with no qualifying Benign or Likely benign expert-panel assertion.	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.