21-42475897-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_080860.4(RSPH1):c.877+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_080860.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RSPH1 | NM_080860.4 | c.877+1G>A | splice_donor_variant, intron_variant | Intron 8 of 8 | ENST00000291536.8 | NP_543136.1 | ||
RSPH1 | NM_001286506.2 | c.763+1G>A | splice_donor_variant, intron_variant | Intron 7 of 7 | NP_001273435.1 | |||
RSPH1 | XM_011529786.2 | c.805+1G>A | splice_donor_variant, intron_variant | Intron 7 of 7 | XP_011528088.1 | |||
RSPH1 | XM_005261208.3 | c.670+1G>A | splice_donor_variant, intron_variant | Intron 6 of 6 | XP_005261265.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RSPH1 | ENST00000291536.8 | c.877+1G>A | splice_donor_variant, intron_variant | Intron 8 of 8 | 1 | NM_080860.4 | ENSP00000291536.3 | |||
RSPH1 | ENST00000398352.3 | c.763+1G>A | splice_donor_variant, intron_variant | Intron 7 of 7 | 5 | ENSP00000381395.3 | ||||
RSPH1 | ENST00000493019.1 | n.2495+1G>A | splice_donor_variant, intron_variant | Intron 7 of 7 | 2 |
Frequencies
GnomAD3 genomes Cov.: 28
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461804Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727212
GnomAD4 genome Cov.: 28
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia Uncertain:1
This sequence change affects a donor splice site in intron 8 of the RSPH1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RSPH1-related conditions. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.