chr10-27935009-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_018076.5(ODAD2):c.2495+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_018076.5 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ODAD2 | NM_018076.5 | c.2495+1G>A | splice_donor_variant, intron_variant | ENST00000305242.10 | NP_060546.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250920Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135598
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461576Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727108
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia 23 Pathogenic:2
Pathogenic, criteria provided, single submitter | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Apr 03, 2013 | This homozygous mutation was predicted to be loss-of-function. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 10, 2023 | Disruption of this splice site has been observed in individual(s) with clinical feature of ARMC4-related conditions (PMID: 23849778). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 242857). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. This sequence change affects a donor splice site in intron 16 of the ARMC4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ARMC4 are known to be pathogenic (PMID: 23849778). This variant is present in population databases (no rsID available, gnomAD 0.0009%). - |
Primary ciliary dyskinesia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 28, 2016 | The c.2495+1G>A variant in ARMC4 has been reported in the homozygous state in 2 siblings with neonatal respiratory distress syndrome, chronic bronchitis/recurre nt sinusitis and tympanic effusion (Hjeij 2013). The c.2495+1G>A variant was abs ent from large population studies. It occurs in the invariant region (+/- 1,2) o f the splice consensus sequence and is predicted to cause altered splicing leadi ng to an abnormal or absent protein. Biallelic loss of function of ARMC4 has bee n associated with primary ciliary dyskinesia. In summary, this variant meets cri teria to be classified as pathogenic for primary ciliary dyskinesia in an autoso mal recessive manner based on its predicted protein impact and biallelic occurre nce in affected individuals. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at