Variant classification summary

NM_000492.4:c.1521_1523del

CFTR · NP_000483.3:p.(Phe508del) · NM_000492.4

GRCh37: chr7:117199644 ATCT>A · GRCh38: chr7:117559590 ATCT>A

Gene: CFTR Transcript: NM_000492.4

Final call

Likely Pathogenic

PS3 strong PM4 moderate PM3 supporting PP5 supporting

Variant details

Gene

CFTR

Transcript

NM_000492.4

Protein

NP_000483.3:p.(Phe508del)

gnomAD AF

0.011931254341569912 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PS3 strong functional evidence shows approximately 3% of wild-type CFTR chloride-channel activity.

2

Likely Pathogenic: PM4 moderate supports a non-repeat-region in-frame deletion removing p.Phe508 from CFTR NBD1.

3

Likely Pathogenic: PM3 supporting shows F508del homozygosity in affected individuals with recessive cystic fibrosis.

4

Likely Pathogenic: PP5 supporting reflects the exact-variant CFTR2 expert-panel Pathogenic ClinVar assertion.

Final determination: Under the generic ACMG/AMP 2015 rules, one Strong pathogenic criterion plus one Moderate and two Supporting pathogenic criteria supports Likely Pathogenic, and no benign rule is satisfied.

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 an in-frame indel.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is an in-frame indel.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no case-specific parental genotypes or confirmed maternity and paternity are provided to establish a de novo variant.
PS3	Met	Met (strong): F508del-CFTR showed approximately 3% of wild-type chloride-channel activity with defective processing and markedly reduced cell-surface delivery.	PMID:7540133
PS4	Not assessed	Not assessed: CFTR2 reports Phe508del in 70% of 39,696 affected individuals, but no compatible control count exists to calculate OR >5.0 with a 95% CI excluding 1.0.	PMID:23974870 PMID:18197057 gnomad_v4
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is an in-frame indel.	generic_acmg_combination_rules
PM2	Not met	Not met: gnomAD v4.1 allele frequency is 0.0119313, far above the generic PM2 supporting threshold of 0.0001.	gnomad_v2 gnomad_v4
PM3	Met	Met, supporting: affected twins were homozygous for F508del, demonstrating the variant on both alleles in this recessive CFTR disorder.	PMID:25697321 PMID:33713579
PM4	Met	Met: the three-nucleotide in-frame deletion removes one amino acid, p.Phe508del, in the functional CFTR NBD1 domain and is not reported as a repeat-region variant.	clinvar PMID:25287046
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is an in-frame indel.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no case-specific evidence demonstrates de novo occurrence without confirmed parental testing.
PP1	Not assessed	Not assessed: no affected relatives or informative meioses are reported to evaluate variant-disease co-segregation.
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is an in-frame indel.	generic_acmg_combination_rules
PP3	N/A	Not applicable: PP3 covers missense or splice-path variants, whereas c.1521_1523del is an in-frame deletion.	generic_acmg_combination_rules
PP4	Not assessed	Not assessed: the required patient phenotype or family history is not provided, so specificity for a single genetic etiology cannot be judged.
PP5	Met	Met: ClinVar's exact CFTR p.Phe508del record has a Pathogenic classification from the CFTR2 expert panel.	clinvar
BA1	Not met	Not met: the highest observed allele frequency is 0.0149425, below the generic BA1 threshold of 0.05.	gnomad_v2 gnomad_v4
BS1	Not assessed	Not assessed: allele frequency is 0.0119313, but CF prevalence, penetrance, and allelic heterogeneity inputs are unavailable for a maximum-credible-frequency assessment.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD v4.1 reports 58 homozygotes, but population records do not document healthy-adult status or absence of cystic fibrosis.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: F508del-CFTR retained approximately 3% of wild-type chloride-channel activity, supporting impaired rather than normal protein function.	PMID:7540133
BS4	Not assessed	Not assessed: no affected relatives have documented genotypes, so lack of segregation cannot be evaluated.
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is an in-frame indel.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no confirmed cis observation was reported, and CFTR-related cystic fibrosis is recessive rather than fully penetrant dominant.	PMID:25697321 PMID:33713579
BP3	N/A	Not applicable: p.Phe508del is an in-frame deletion in the characterized CFTR NBD1 domain, not a deletion in a functionless repetitive region.	clinvar PMID:25287046
BP4	N/A	Not applicable: BP4 covers missense or splice-path variants, whereas c.1521_1523del is an in-frame deletion altering protein length.	generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no alternate molecular basis for disease is documented in the interpreted case.
BP6	Not met	Not met: the exact ClinVar expert-panel classification is Pathogenic, with no Benign or Likely benign expert-panel assertion.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is an in-frame indel.	generic_acmg_combination_rules

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