Variant classification summary

NM_000492.4:c.3846G>A

CFTR · NP_000483.3:p.(Trp1282Ter) · NM_000492.4

GRCh37: chr7:117282620 G>A · GRCh38: chr7:117642566 G>A

Gene: CFTR Transcript: NM_000492.4

Final call

Pathogenic

PVS1 very strong PS3 supporting PS4 strong PM2 supporting PP5 supporting

Variant details

Gene

CFTR

Transcript

NM_000492.4

Protein

NP_000483.3:p.(Trp1282Ter)

gnomAD AF

0.0002609435122376929 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 very strong reflects the CFTR nonsense loss-of-function consequence producing W1282X.

2

Pathogenic: PS3 supporting reflects abolished chloride transport with restoration after correction.

3

Pathogenic: PS4 strong reflects a case-control OR of 199.6 with a confidence interval excluding 1.0.

4

Pathogenic: PM2 supporting reflects a gnomAD v4.1 grpmax FAF of 6.312e-05.

5

Pathogenic: PP5 supporting reflects the CFTR2 expert-panel Pathogenic classification in ClinVar.

Final determination: Under the generic ACMG/AMP 2015 fallback, one very strong pathogenic criterion plus one strong pathogenic criterion satisfies the Pathogenic combination rule; supporting criteria do not change that call.

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	Met	Met at very strong strength: CFTR c.3846G>A is a nonsense variant producing W1282X, with minimal functional protein and abolished chloride transport.	pvs1_generic_framework PMID:23974870 PMID:32332735 PMID:15371902
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is a nonsense variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no documented de novo finding with both maternity and paternity confirmed and no family history.
PS3	Met	Met, supporting: W1282X abolished chloride transport, while correction restored CFTR protein to approximately 10% of wild-type levels and restored channel activity.	PMID:32332735
PS4	Met	Met: W1282X shows a computed case-control OR of 199.6 (95% CI 159.7-249.4), exceeding the >5.0 threshold with a confidence interval excluding 1.0.	PMID:15371902 gnomad_v4
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is a nonsense variant.	generic_acmg_combination_rules
PM2	Met	Met at supporting: gnomAD v4.1 grpmax FAF is 6.312e-05, below the generic PM2 supporting threshold of 0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no parent/offspring phase testing or affected-proband genotype demonstrates c.3846G>A in trans with a pathogenic CFTR variant.	clinvar PMID:15371902
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a nonsense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is a nonsense variant.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no documented assumed de novo occurrence or parental testing information is available.
PP1	Not assessed	Not assessed: no multiple affected relatives, informative meioses, or variant-disease segregation data are documented.
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is a nonsense variant.	generic_acmg_combination_rules
PP3	N/A	Not applicable: c.3846G>A is a nonsense, protein-truncating variant outside the generic PP3 missense or splice-region/intronic scope.
PP4	Not assessed	Not assessed: the patient's phenotype and family history are not provided, so phenotype specificity for a single genetic etiology cannot be judged.
PP5	Met	Met: ClinVar reports the exact c.3846G>A (p.Trp1282Ter) variant as Pathogenic by the CFTR2 expert panel, satisfying the instructed PP5 rule.	clinvar
BA1	Not met	Not met: gnomAD grpmax FAF is 6.312e-05, far below the generic BA1 threshold of 0.05 despite a 0.943% Ashkenazi Jewish popmax point estimate.	gnomad_v2 gnomad_v4 clinvar PMID:15371902
BS1	Not met	Not met: the highest qualifying gnomAD filtering FAF is 8.828e-05, below the generic BS1 threshold of 0.01; Ashkenazi Jewish popmax AF is not the permitted metric.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD v4.1 shows one homozygote, but it provides no evidence that the individual was a healthy adult beyond the expected age of CF penetrance.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: W1282X abolished chloride transport and produced minimal functional CFTR protein, while correction restored protein expression and channel activity.	PMID:32332735
BS4	Not assessed	Not assessed: no affected relatives with documented negative testing for NM_000492.4:c.3846G>A are reported.
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is a nonsense variant.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no documented cis pathogenic variant or phase-resolved trans observation satisfies either BP2 allelic configuration.	clinvar
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a nonsense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: c.3846G>A is a nonsense, protein-truncating variant, so a no-splice-impact prediction cannot support generic BP4.
BP5	Not assessed	Not assessed: no evidence shows that this case has an alternate molecular basis for disease in addition to c.3846G>A.
BP6	Not assessed	Not assessed: no exact-variant reputable benign or likely benign assertion is available; the identified expert-panel classification is Pathogenic.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a nonsense variant.	generic_acmg_combination_rules

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