rs727502967
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_001277115.2(DNAH11):c.4879C>T(p.Arg1627Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
DNAH11
NM_001277115.2 missense
NM_001277115.2 missense
Scores
11
5
1
Clinical Significance
Conservation
PhyloP100: 2.46
Genes affected
DNAH11 (HGNC:2942): (dynein axonemal heavy chain 11) This gene encodes a ciliary outer dynein arm protein and is a member of the dynein heavy chain family. It is a microtubule-dependent motor ATPase and has been reported to be involved in the movement of respiratory cilia. Mutations in this gene have been implicated in causing Kartagener Syndrome (a combination of situs inversus totalis and Primary Ciliary Dyskinesia (PCD), also called Immotile Cilia Syndrome 1 (ICS1)) and male sterility. [provided by RefSeq, Mar 2013]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.959
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DNAH11 | ENST00000409508.8 | c.4879C>T | p.Arg1627Cys | missense_variant | 28/82 | 5 | NM_001277115.2 | ENSP00000475939.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152176Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000803 AC: 2AN: 249020Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135102
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GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461416Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11AN XY: 726990
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74344
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 26, 2021 | The p.R1627C pathogenic mutation (also known as c.4879C>T), located in coding exon 28 of the DNAH11 gene, results from a C to T substitution at nucleotide position 4879. The arginine at codon 1627 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been detected in multiple individuals with a clinical diagnosis or suspicion of primary ciliary dyskinesia, who have another pathogenic mutation in DNAH11 (internal Ambry data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 15, 2022 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1627 of the DNAH11 protein (p.Arg1627Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with heterotaxy and primary ciliary dyskinesia (Invitae). ClinVar contains an entry for this variant (Variation ID: 163104). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DNAH11 protein function. This variant disrupts the p.Arg1627 amino acid residue in DNAH11. Other variant(s) that disrupt this residue have been observed in individuals with DNAH11-related conditions (PMID: 31772028; Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 12, 2024 | Variant summary: DNAH11 c.4879C>T (p.Arg1627Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249020 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4879C>T in individuals affected with Primary Ciliary Dyskinesia 7 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 163104). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 27, 2013 | The Arg1627Cys variant in DNAH11 has not been previously reported in individuals with lung disease or in large population studies. This residue is conserved in evolution and computational analyses (biochemical amino acid properties, AlignGV GD, PolyPhen2, and SIFT) predict that this variant will impact the normal functi on of the protein. In summary, this information is insufficient to establish the the clinical significance of the Arg1627Cys variant. - |
Primary ciliary dyskinesia 7 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Oct 20, 2020 | This DNAH11 variant (rs727502967) is rare (<0.1%) in a large population dataset (gnomAD: 3/280426 total alleles; 0.001%; no homozygotes) and has not been reported in ClinVar nor the literature, to our knowledge. Two bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is highly evolutionarily conserved across most species assessed. Due to insufficient evidence that this variant is deleterious, we consider the clinical significance of c.4879C>T to be uncertain at this time. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
.;.;D
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;D;.
REVEL
Pathogenic
Sift
Pathogenic
.;D;.
Vest4
MutPred
Gain of catalytic residue at P1631 (P = 0.1768);Gain of catalytic residue at P1631 (P = 0.1768);.;
MVP
ClinPred
D
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at