Variant classification summary

NM_000492.4:c.1624G>T

CFTR · NP_000483.3:p.(Gly542Ter) · NM_000492.4

GRCh37: chr7:117227832 G>T · GRCh38: chr7:117587778 G>T

Gene: CFTR Transcript: NM_000492.4

Final call

Pathogenic

PVS1 very strong PS4 strong PP5 supporting

Variant details

Gene

CFTR

Transcript

NM_000492.4

Protein

NP_000483.3:p.(Gly542Ter)

gnomAD AF

0.00036287621268888174 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 very strong supports a CFTR loss-of-function effect from the exon 12 nonsense variant p.Gly542Ter.

2

Pathogenic: PS4 strong is supported by the markedly increased G542X frequency in affected individuals compared with gnomAD NFE controls.

3

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

Final determination: Under the generic ACMG/AMP 2015 fallback, one very strong pathogenic criterion plus one strong pathogenic criterion supports a Pathogenic classification; PP5 supporting is additional evidence.

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, very strong: CFTR c.1624G>T is an exon 12 nonsense variant causing p.Gly542Ter in a gene with an established germline loss-of-function disease mechanism.	pvs1_generic_framework pvs1_gene_context PMID:25741868 PMID:23974870
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: confirmed maternity, paternity, de novo status, and absence of family history are not documented for the proband.
PS3	Not assessed	Not assessed: no cited study directly measured c.1624G>T/p.G542* function; PMID:23974870 addressed premature-termination variants generally rather than this variant.	PMID:23974870 PMID:7691345
PS4	Met	Met: G542X occurred in 14/370 French CF chromosomes versus 476/1,178,404 gnomAD NFE alleles, OR 93.67 (95% CI 54.52–160.93), exceeding OR >5 with CI excluding 1.	PMID:1723032 gnomad_v4
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is a nonsense variant.	generic_acmg_combination_rules
PM2	Not met	Not met: the lower all-comers AF is 0.000322338, above the generic PM2 cutoff of 0.0001.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: G542X appeared in compound heterozygotes, but parental or offspring testing establishing phase was not documented.	PMID:1723032
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 case-specific evidence establishes assumed de novo origin or parental testing for this variant.
PP1	Not assessed	Not assessed: G542X occurred on 14 of 370 screened CF chromosomes, but affected-relative co-segregation and meioses are not reported.	PMID:1723032
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.1624G>T is a nonsense variant, outside generic PP3 scope regardless of its SpliceAI max delta of 0.13.	pvs1_variant_assessment
PP4	Not assessed	Not assessed: no patient-specific phenotype or family history is available to test the PP4 requirement for a highly specific single-etiology disease presentation.
PP5	Met	Met: the exact CFTR c.1624G>T variant has a Pathogenic CFTR2 expert-panel classification in ClinVar, satisfying the supplied PP5 rule.	clinvar
BA1	Not met	Not met: maximum qualifying grpmax FAF is 0.00055223, far below the 0.05 BA1 threshold.	gnomad_v2 gnomad_v4 clinvar PMID:25741868
BS1	Not met	Not met: maximum qualifying grpmax FAF is 0.00055223, below the generic 0.01 BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v2.1 and v4.1 each report zero homozygotes for this variant.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no cited study showed normal CFTR function or splicing for c.1624G>T/p.G542*; available assays tested other variants or variant classes.	PMID:23974870 PMID:7691345
BS4	Not assessed	Not assessed: no affected relatives without G542X are documented, so lack of segregation cannot be evaluated.	PMID:1723032
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is a nonsense variant.	generic_acmg_combination_rules
BP2	Not met	Not met: G542X was reported in trans in recessive CF, not the required dominant-trans or any-inheritance cis configuration.	PMID:1723032
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: BP4 excludes nonsense variants, so SpliceAI max delta 0.13 cannot support absence of gene-product impact.	pvs1_variant_assessment
BP5	Not assessed	Not assessed: no case-level evidence shows the exact variant alongside an alternate molecular basis for the patient's disease.
BP6	Not met	Not met: the exact variant has a Pathogenic CFTR2 expert-panel classification and no benign expert-panel classification is present.	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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