About DNAH11
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
DNAH11 c.4879C>T, p.(Arg1627Cys)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
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.
PP3Supporting
PP3 · supporting
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP3 supporting; combination = 2 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
25 / 1,613,592 alleles
gnomAD v4.1: 25 / 1,613,592 alleles. Recorded AF 1.54934e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.0698e-05; MAF= 0.00107%, 3/280426 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.83318e-05; MAF= 0.00283%, 1/35296 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
6 reported laboratory submissions
4 Uncertain significance · 1 Pathogenic · 1 Likely pathogenic. ClinVar API review status: criteria provided, conflicting classifications.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV60977423, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 22 not met · 0 not assessed · 2 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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).
No criteria match.
Met · 2
PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF = 1.0698e-05 (3/280
- 426 alleles
- 0 homozygotes)
- gnomAD v4.1 AF = 1.5493e-05 (25/1
- 613
- 592 alleles
- 0 homozygotes
- grpmax FAF = 1.221e-05)
- Absent from gnomAD-Canada v1.0
Sources
PP3 SupportingIn 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. Details ▾Hide ▴
Evidence considered
- REVEL score = 0.887 (>0.75 damaging threshold)
- BayesDel score = 0.430511
- SpliceAI max delta = 0.00 (no splice impact)
Sources
Not met · 22 · evaluated, threshold not reached
PS1 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. Details ▾Hide ▴
Evidence considered
- No ClinVar entries for an alternative nucleotide substitution producing p.Arg1627Cys.
Still missing
- No established pathogenic variant at codon 1627 with a different nucleotide change.
PS2 No de novo occurrence data with confirmed maternity/paternity is available for this variant. Details ▾Hide ▴
Still missing
- No de novo data in ClinVar submissions or literature.
PS3 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. Details ▾Hide ▴
Evidence considered
- No variant-specific or range-based functional data identified in full-text review of available publications.
Still missing
- No functional study tests this variant or a systematically characterized range covering residue 1627.
PS4 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. Details ▾Hide ▴
Evidence considered
- No variant-specific case or case-control data in ClinVar submissions or literature.
Still missing
- No case-control study or cohort enumerating this variant.
PM1 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. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: residue not significant
- exact variant not listed.
Still missing
- No critical functional domain characterization at residue 1627 in the available evidence.
PM5 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. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned 0 same-residue pathogenic comparators.
Still missing
- No established pathogenic variant at codon 1627 with a different amino acid substitution.
PM6 No de novo occurrence has been reported for this variant in any ClinVar submission or reviewed publication. Details ▾Hide ▴
Still missing
- No de novo data available.
PP1 No co-segregation data is available for this variant. No family-based studies were identified in the literature or ClinVar submissions. Details ▾Hide ▴
Still missing
- No family co-segregation data available.
PP2 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. Details ▾Hide ▴
Evidence considered
- DNAH11 is a large gene with numerous missense variants in gnomAD
- missense constraint data is insufficient to support PP2.
Still missing
- No gene-level missense constraint metric (e.g.
- Z-score) available to support PP2.
PP4 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. Details ▾Hide ▴
Still missing
- No patient-specific phenotype data for this exact variant.
PP5 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. Details ▾Hide ▴
Evidence considered
- ClinVar: 4 VUS
- 1 Pathogenic
- 1 Likely pathogenic
- no expert panel
- single-submitter review status.
Still missing
- Lack of expert panel consensus
- majority VUS classification.
Sources
BA1 The maximum population allele frequency is 0.00155% in gnomAD v4.1, which is well below the 1% BA1 threshold. Details ▾Hide ▴
BS1 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. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 highest subpopulation AF = 0.00333% (far below BS1 >0.3% threshold)
Sources
BS2 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. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 25 heterozygous carriers in population controls
- but no individual phenotype data to confirm healthy adult status specific to this recessive condition.
Still missing
- No individual-level phenotype data for gnomAD carriers.
BS3 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. Details ▾Hide ▴
Evidence considered
- No benign functional data identified for this variant.
Still missing
- No functional data of any kind available for this variant.
BS4 No segregation data is available to evaluate lack of co-segregation with disease. Details ▾Hide ▴
Still missing
- No family segregation data available.
BP1 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. Details ▾Hide ▴
Evidence considered
- DNAH11 PCD is associated with both missense and truncating variants
- missense is a known disease mechanism.
BP2 No evidence that this variant has been observed in trans with a known pathogenic variant in DNAH11 in an unaffected individual. Details ▾Hide ▴
Still missing
- No trans phase data available.
BP4 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. Details ▾Hide ▴
Evidence considered
- REVEL 0.887 (damaging
- >0.75)
- BayesDel 0.43 (intermediate)
- SpliceAI max delta 0.00
Sources
BP5 No evidence that this variant has been observed in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
- No alternate molecular basis data available.
BP6 No reputable source reports this variant as benign. The ClinVar aggregate classification is Uncertain Significance. Details ▾Hide ▴
Evidence considered
- ClinVar classification: VUS
- no benign assertion from any submitter.
Sources
PS5 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. Details ▾Hide ▴
Evidence considered
- ClinVar variation ID 163104
- no expert panel review
- majority VUS classification.
Still missing
- No expert panel pathogenicity assertion available.
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_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). Details ▾Hide ▴
Evidence considered
- Missense substitution at position 4879
- variant bucket classified as 'other' per PVS1 variant assessment.
Sources
BP7 N/AThis is a missense variant, not a synonymous or intronic variant. BP7 is not applicable. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- DNAH11
- Transcript
- NM_001277115.2
- Coding (HGVS c.)
- NM_001277115.2:c.4879C>T
- Protein (HGVS p.)
- NP_001264044.1:p.(Arg1627Cys)
- GRCh38
- chr7:21639000 C>T
- GRCh37
- chr7:21678618 C>T
- ClinVar
- 2377466, 163104
- COSMIC
- COSV60977423
Gene diagram
Every interpreted variant in DNAH11, mapped onto the exon structure of NM_001277115.2. Select a row to find it on the plot.
DNAH11NM_001277115.2
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in DNAH11
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
25 / 1,613,592 alleles
AF 1.55e-05 · 0 homozygotes · FAF 1.22e-05
gnomAD v2.1
3 / 280,426 alleles
AF 1.07e-05 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.5e-05 · 25 / 1,613,592 alleles · 0 hom · FAF 1.2e-05
| Admixed American2 / 59,986 | 3.3e-05 |
| European (non-Finnish)22 / 1,179,726 | 1.9e-05 |
| South Asian1 / 91,026 | 1.1e-05 |
0 alternate alleles recorded in 7 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 1.1e-05 · 3 / 280,426 alleles · 0 hom
| Admixed American1 / 35,296 | 2.8e-05 |
| European (non-Finnish)2 / 128,354 | 1.6e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.54934e-05; MAF= 0.00155%, 25/1613592 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.33411e-05; MAF= 0.00333%, 2/59986 alleles, homozygotes = 0); grpmax FAF= 1.221e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.0698e-05; MAF= 0.00107%, 3/280426 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.83318e-05; MAF= 0.00283%, 1/35296 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.887
- BayesDel
- 0.431
How the predictions were used
PP3 SupportingIn 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. Details ▾Hide ▴
Evidence considered
- REVEL score = 0.887 (>0.75 damaging threshold)
- BayesDel score = 0.430511
- SpliceAI max delta = 0.00 (no splice impact)
Sources
BP4 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. Details ▾Hide ▴
Evidence considered
- REVEL 0.887 (damaging
- >0.75)
- BayesDel 0.43 (intermediate)
- SpliceAI max delta 0.00
Sources
BP7 N/AThis is a missense variant, not a synonymous or intronic variant. BP7 is not applicable. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.887. BayesDel score = 0.430511.
4 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 24033266 ↗A systematic approach to assessing the clinical significance of genetic variants.Duzkale H et al. · 2013Describes a systematic variant assessment tool (VAT) for evaluating clinical significance of genetic variants using ACMG criteria. DNAH11 NM_001277115.2:c.4879C>T was not identified in this paper.Does not name this variant
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015ACMG/AMP consensus standards and guidelines for the interpretation of sequence variants. This is a framework document describing the classification criteria; it does not discuss any specific variant.Does not name this variant
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PMID 20301301 ↗Primary Ciliary Dyskinesia.Adam MP et al. · 1993GeneReviews overview of primary ciliary dyskinesia, covering clinical characteristics, genetic heterogeneity, and diagnostic approaches. DNAH11 is listed among PCD-associated genes but NM_001277115.2:c.4879C>T is not discussed.Does not name this variant
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PMID 31772028 ↗Deep phenotyping, including quantitative ciliary beating parameters, and extensive genotyping in primary ciliary dyskinesia.Blanchon S et al. · 2020Prospective study of deep ciliary phenotyping and extensive genotyping in 75 primary ciliary dyskinesia patients, including 13 with biallelic DNAH11 mutations. Describes that patients with severe biallelic DNAH11 mutations show impaired ciliary beating, while missense variants may result in milder alterations. NM_001277115.2:c.4879C>T is not specifically mentioned; individual patient genotypes are listed in supplementary material not included in the full text.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
25 / 1,613,592 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
4 Uncertain significance · 1 Pathogenic · 1 Likely pathogenic
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/163104/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-21678618-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-21639000-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-21639000-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001277115.2%3Ac.4…
- OncoKB ↗www.oncokb.org/gene/DNAH11/R1627C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=151020744
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.54934e-05; MAF= 0.00155%, 25/1613592 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.33411e-05; MAF= 0.00333%, 2/59986 alleles, homozygotes = 0); grpmax FAF= 1.221e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.0698e-05; MAF= 0.00107%, 3/280426 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.83318e-05; MAF= 0.00283%, 1/35296 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Pathogenic (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 163104)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.887. BayesDel score = 0.430511.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV60977423, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.