NM_001277115.2:c.4879C>T

DNAH11 · NP_001264044.1:p.(Arg1627Cys) · NM_001277115.2

GRCh37: chr7:21678618 C>T · GRCh38: chr7:21639000 C>T

Gene: DNAH11 Transcript: NM_001277115.2

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

DNAH11

Transcript

NM_001277115.2

Protein

NP_001264044.1:p.(Arg1627Cys)

gnomAD AF

1.5493383705422435e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001277115.2:c.4879C>T (p.Arg1627Cys) is a missense variant in DNAH11, a gene associated with autosomal recessive primary ciliary dyskinesia (PCD) and heterotaxy syndromes.

This variant is extremely rare in population databases: gnomAD v2.1 AF = 0.00107% (3/280,426 alleles), gnomAD v4.1 AF = 0.00155% (25/1,613,592 alleles), and it is absent from gnomAD-Canada, with no homozygotes observed in any population database (PM2_supporting).

In silico prediction tools support a deleterious effect, with a REVEL score of 0.887 exceeding the damaging threshold (PP3_supporting).

SpliceAI predicts no splicing impact (max delta score = 0.00), and the variant does not lie in a statistically significant mutational hotspot.

This variant has been reported in ClinVar with conflicting classifications: four clinical laboratories classify it as Uncertain Significance, one as Pathogenic, and one as Likely Pathogenic. No expert panel review has been performed (ClinVar Variation ID: 163104).

The variant has been observed somatically in COSMIC (COSV60977423, n = 2).

No variant-specific functional data, case-control studies, segregation data, or de novo reports were identified in the reviewed literature. The five publications cited by ClinVar submitters are either methodology/guideline papers (PMID:24033266, PMID:25741868, PMID:28492532), a general GeneReviews overview (PMID:20301301), or a PCD cohort study that does not specifically mention c.4879C>T (PMID:31772028).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	NM_001277115.2:c.4879C>T is a missense variant (p.Arg1627Cys) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for PVS1 under the ClinGen SVI PVS1 framework (PMC6185798).	pvs1_generic_framework
PS1	Not met	No evidence of an alternative nucleotide change at codon 1627 that results in the same p.Arg1627Cys missense and has been established as pathogenic. PM5 candidate harvesting returned no comparators.
PS2	Not met	No de novo occurrence data with confirmed maternity/paternity is available for this variant.
PS3	Not met	No experimental functional data was identified for NM_001277115.2:c.4879C>T (p.Arg1627Cys) in any reviewed publication. The variant is not directly tested, nor does it fall within a systematically characterized range from any published functional study. REVEL score of 0.887 is in silico prediction, not experimental evidence, and does not satisfy PS3 requirements.
PS4	Not met	No variant-specific case-control or cohort data was identified. Blanchon et al. (PMID:31772028) reports 13 DNAH11-mutated PCD patients but does not mention NM_001277115.2:c.4879C>T. The GeneReviews entry (PMID:20301301) is a general overview of PCD and does not reference this variant.
PS5	Not met	No ClinGen-approved expert panel classification exists for this variant. ClinVar submissions include 4 VUS, 1 Pathogenic, and 1 Likely pathogenic — all at single-submitter review status with no expert panel consensus.
PM1	Not met	The variant does not lie within a statistically significant mutational hotspot as assessed by cancerhotspots.org. No domain-level functional characterization evidence was identified in the literature for the region surrounding residue 1627 that would support PM1.
PM2	Met	This variant is absent or extremely rare in population databases. gnomAD v2.1 AF = 0.00107% (3/280,426 alleles), gnomAD v4.1 AF = 0.00155% (25/1,613,592 alleles; grpmax FAF = 1.221e-05), and it is absent from gnomAD-Canada. All population frequencies are well below the 0.1% PM2 threshold. No homozygotes have been observed.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	Automated PM5 candidate harvesting did not identify any same-residue comparator variants at position 1627 in DNAH11 with a different amino acid change classified as pathogenic. Manual review confirms no alternative pathogenic missense at this residue in ClinVar or the literature.
PM6	Not met	No de novo occurrence has been reported for this variant in any ClinVar submission or reviewed publication.
PP1	Not met	No co-segregation data is available for this variant. No family-based studies were identified in the literature or ClinVar submissions.
PP2	Not met	PP2 requires a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. DNAH11 is a large gene (82 exons) with substantial benign missense variation in gnomAD and is associated with autosomal recessive primary ciliary dyskinesia; there is insufficient evidence that DNAH11 meets the stringent PP2 constraint thresholds.
PP3	Met	In silico prediction tools support a deleterious effect: REVEL score is 0.887, which exceeds the 0.75 threshold for damaging prediction. BayesDel score is 0.43 (intermediate). SpliceAI predicts no splicing impact (max delta = 0.00). The REVEL score provides supporting computational evidence of pathogenicity.	revel bayesdel spliceai
PP4	Not met	No patient-specific phenotypic data is available for this variant. The variant has been reported in the context of DNAH11-associated PCD only at the gene level; no individual phenotype for a carrier of NM_001277115.2:c.4879C>T has been described.
PP5	Not met	Although one clinical laboratory (Fulgent Genetics) classified this variant as Likely Pathogenic and another as Pathogenic, four additional clinical laboratories classified it as Uncertain Significance. The aggregate ClinVar classification is VUS with single-submitter review status and no expert panel endorsement. Credible but contested, PP5 requires a reputable source with a confident pathogenic assertion, which is not met here given the preponderance of VUS classifications.	clinvar
BA1	Not met	The maximum population allele frequency is 0.00155% in gnomAD v4.1, which is well below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	The maximum population allele frequency is 0.00333% in the Admixed American subpopulation (gnomAD v4.1), which is well below the 0.3% BS1 threshold.	gnomad_v4
BS2	Not met	No evidence that this variant has been observed in a healthy adult individual in a context sufficient to meet BS2. The gnomAD carriers (25 heterozygotes in v4.1) are population-level observations without individual-level phenotype confirmation. For an autosomal recessive disorder like PCD, heterozygous carrier status alone does not satisfy BS2.
BS3	Not met	No functional studies demonstrating a benign or normal effect for this variant were identified in the literature. All reviewed publications either do not mention this variant or are methodology/guideline papers.
BS4	Not met	No segregation data is available to evaluate lack of co-segregation with disease.
BP1	Not met	BP1 applies when a missense variant occurs in a gene where only truncating variants cause disease. DNAH11-associated primary ciliary dyskinesia is caused by both missense and truncating variants. Published cohorts (e.g., Blanchon et al., PMID:31772028) include patients with biallelic missense genotypes, demonstrating that missense variants are a recognized disease mechanism in DNAH11.
BP2	Not met	No evidence that this variant has been observed in trans with a known pathogenic variant in DNAH11 in an unaffected individual.
BP4	Not met	Multiple in silico prediction tools support a deleterious effect: REVEL score is 0.887 (damaging), BayesDel score is 0.43 (intermediate, not clearly benign). SpliceAI shows no splicing impact, but this does not outweigh the damaging REVEL prediction. BP4 is not met because the computational evidence does not support a benign interpretation.	revel bayesdel spliceai
BP5	Not met	No evidence that this variant has been observed in a case with an alternate molecular basis for disease.
BP6	Not met	No reputable source reports this variant as benign. The ClinVar aggregate classification is Uncertain Significance.	clinvar
BP7	N/A	This is a missense variant, not a synonymous or intronic variant. BP7 is not applicable.

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.