Variant classification summary

NM_000492.4:c.3718-2477C>T

CFTR · NP_000483.3:p.? · NM_000492.4

GRCh37: chr7:117280015 C>T · GRCh38: chr7:117639961 C>T

Gene: CFTR Transcript: NM_000492.4

Final call

VUS

PS3 supporting PM3 moderate PP5 supporting

Variant details

Gene

CFTR

Transcript

NM_000492.4

Protein

NP_000483.3:p.?

gnomAD AF

0.00011841793637009553 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: exact-variant RT-PCR demonstrated an aberrant 84-bp cryptic exon and reduced correctly spliced CFTR RNA.

2

PM3 moderate: an affected CF fetus carried the variant in trans with pathogenic F508del.

3

PP5 supporting: the CFTR2 ClinVar expert panel classified the exact variant as Pathogenic.

Final determination: Under generic ACMG/AMP 2015 rules, 1 moderate plus 2 supporting pathogenic criteria does not satisfy a pathogenic or likely pathogenic combination, and no benign rule is satisfied; therefore the call is VUS.

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: c.3718-2477C>T is a deep-intronic C>T SNV with NP_000483.3:p.?, not a canonical splice-site or other null variant named by PVS1.	pvs1_variant_assessment PMID:10351951
PS1	N/A	Not applicable: the deep-intronic variant has protein consequence p.? and creates an 84-bp cryptic exon rather than an amino-acid substitution.	PMID:10351951
PS2	Not assessed	Not assessed: no documented de novo occurrence, confirmed maternity and paternity, or absence of family history is available for this patient.
PS3	Met	Met at supporting strength: exact-variant RT-PCR found an 84-bp cryptic exon with an in-frame stop codon and normal CFTR RNA as low as 1% in ileum.	PMID:10351951
PS4	Not met	Not met: no exact-variant case-control counts, odds ratio, relative risk, or confidence interval were verified against the PS4 threshold of OR/RR >5.0 with CI excluding 1.0.	PMID:15371902
PM1	N/A	Not applicable: p.? provides no protein residue to place in a mutational hotspot or critical functional domain.	PMID:10351951
PM2	Not met	Not met: gnomAD v4.1 grpmax FAF=0.00016885 exceeds the PM2 supporting cutoff of 0.0001, although the variant is rare.	gnomad_v4 gnomad_v2 PMID:25741868
PM3	Met	Met: an affected CF fetus was compound heterozygous for c.3718-2477C>T and F508del, directly documenting the assessed variant in trans with a pathogenic allele.	PMID:10351951
PM4	N/A	Not applicable: the variant is a deep-intronic C>T SNV with p.?, not an in-frame coding indel or stop-loss protein-length change.	pvs1_variant_assessment PMID:10351951
PM5	N/A	Not applicable: the splice variant has protein consequence p.? and no amino-acid residue for an alternate-missense comparison.	PMID:10351951
PM6	Not assessed	Not assessed: no patient-specific evidence indicates that this variant was assumed de novo without confirmed maternity and paternity.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or variant genotypes across a family are documented to evaluate co-segregation.
PP2	N/A	Not applicable: PP2 requires a missense variant, but this variant is deep intronic with protein consequence p.? and aberrant splicing.	PMID:10351951
PP3	Not met	Not met: SpliceAI max delta 0.162 is below the generic PP3 supporting threshold of 0.2 for this intronic variant.	spliceai
PP4	Not assessed	Not assessed: a sufficiently specific patient phenotype or family history supporting a single genetic etiology was not provided.
PP5	Met	Met: ClinVar variation 7166 records the exact variant as Pathogenic by the CFTR2 expert panel, meeting the specified PP5 source requirement.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF=0.00016885 is below the BA1 threshold of 0.05, despite the Ashkenazi Jewish point estimate of 0.00172911.	gnomad_v4 gnomad_v2 clinvar PMID:25741868
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF=0.00016885 is below the generic BS1 default of 0.01 and does not show an unexpectedly high disorder allele frequency.	gnomad_v4 clinvar
BS2	Not met	Not met: gnomAD v4.1 observed 0 homozygotes among 18 alleles, with no documented healthy adult homozygote for this autosomal-recessive CFTR variant.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no well-established benign functional study was identified, while the available exact-variant assay instead showed aberrant splicing and reduced normal CFTR RNA.
BS4	Not assessed	Not assessed: no affected relatives without the variant or pedigree evidence addressing phenocopies and alternative pathogenic variants is documented.
BP1	N/A	Not applicable: BP1 requires a missense variant, but this deep-intronic variant has protein consequence p.? and a splice mechanism.	PMID:10351951
BP2	Not met	Not met: the observed compound heterozygosity is trans in recessive CFTR, while BP2 requires trans in a fully penetrant dominant disorder or cis in any inheritance pattern.	PMID:10351951
BP3	N/A	Not applicable: c.3718-2477C>T is a deep-intronic C>T SNV, not an in-frame deletion or insertion in a repetitive region.	pvs1_variant_assessment PMID:10351951
BP4	Not met	Not met: SpliceAI max delta 0.162 exceeds the generic BP4 supporting threshold of 0.1 for this intronic variant.	spliceai
BP5	Not assessed	Not assessed: no case-level alternate molecular diagnosis was documented for a patient carrying this variant.
BP6	Not met	Not met: the exact-variant ClinVar expert-panel record is Pathogenic, with no Benign or Likely benign expert-panel assertion supporting BP6.	clinvar
BP7	N/A	Not applicable: the variant is intronic, whereas BP7 applies only to synonymous variants with no predicted splice impact and low conservation.

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