rs748101941
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_018076.5(ODAD2):āc.1922T>Cā(p.Leu641Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,614,044 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 Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000053 ( 0 hom., cov: 31)
Exomes š: 0.000051 ( 0 hom. )
Consequence
ODAD2
NM_018076.5 missense
NM_018076.5 missense
Scores
12
5
2
Clinical Significance
Conservation
PhyloP100: 8.89
Genes affected
ODAD2 (HGNC:25583): (outer dynein arm docking complex subunit 2) The protein encoded by this gene contains ten Armadillo repeat motifs (ARMs) and one HEAT repeat, and is thought to be involved in ciliary and flagellar movement. This protein has been shown to localize to the ciliary axonemes and at the ciliary base of respiratory cells. Studies indicate that mutations in this gene cause partial outer dynein arm (ODA) defects in respiratory cilia. The cilia of cells with mutations in this gene displayed either reduced ciliary beat frequency and amplitude, or, complete immotility. Some individuals with primary ciliary dyskensia (PCD) have been shown to have mutations in this gene. PCD is characterized by chronic airway disease and left/right body asymmetry defects. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]
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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, 0.974
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ODAD2 | NM_018076.5 | c.1922T>C | p.Leu641Pro | missense_variant | 13/20 | ENST00000305242.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ODAD2 | ENST00000305242.10 | c.1922T>C | p.Leu641Pro | missense_variant | 13/20 | 1 | NM_018076.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152204Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251006Hom.: 0 AF XY: 0.0000737 AC XY: 10AN XY: 135632
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GnomAD4 exome AF: 0.0000506 AC: 74AN: 1461840Hom.: 0 Cov.: 31 AF XY: 0.0000454 AC XY: 33AN XY: 727224
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GnomAD4 genome AF: 0.0000526 AC: 8AN: 152204Hom.: 0 Cov.: 31 AF XY: 0.0000807 AC XY: 6AN XY: 74360
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 05, 2022 | The c.1922T>C (p.L641P) alteration is located in exon 13 (coding exon 12) of the ARMC4 gene. This alteration results from a T to C substitution at nucleotide position 1922, causing the leucine (L) at amino acid position 641 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Primary ciliary dyskinesia 23 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 09, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 641 of the ARMC4 protein (p.Leu641Pro). This variant is present in population databases (rs748101941, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ARMC4-related conditions. ClinVar contains an entry for this variant (Variation ID: 241258). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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