chr21-42485807-G-T
Variant summary
Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3PP5_Moderate
The NM_080860.4(RSPH1):c.366-3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_080860.4 splice_region, intron
Scores
Clinical Significance
Conservation
Publications
- primary ciliary dyskinesia 24Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
- primary ciliary dyskinesiaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RSPH1 | NM_080860.4 | c.366-3C>A | splice_region_variant, intron_variant | Intron 4 of 8 | ENST00000291536.8 | NP_543136.1 | ||
RSPH1 | NM_001286506.2 | c.252-3C>A | splice_region_variant, intron_variant | Intron 3 of 7 | NP_001273435.1 | |||
RSPH1 | XM_011529786.2 | c.366-3C>A | splice_region_variant, intron_variant | Intron 4 of 7 | XP_011528088.1 | |||
RSPH1 | XM_005261208.3 | c.159-3C>A | splice_region_variant, intron_variant | Intron 2 of 6 | XP_005261265.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RSPH1 | ENST00000291536.8 | c.366-3C>A | splice_region_variant, intron_variant | Intron 4 of 8 | 1 | NM_080860.4 | ENSP00000291536.3 | |||
RSPH1 | ENST00000493019.1 | n.989C>A | non_coding_transcript_exon_variant | Exon 4 of 8 | 2 | |||||
RSPH1 | ENST00000398352.3 | c.252-3C>A | splice_region_variant, intron_variant | Intron 3 of 7 | 5 | ENSP00000381395.3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461800Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727218 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia 24 Pathogenic:1
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Primary ciliary dyskinesia Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 66988). This variant has been observed in individual(s) with primary ciliary dyskinesia (PMID: 23993197). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 4 of the RSPH1 gene. It does not directly change the encoded amino acid sequence of the RSPH1 protein. It affects a nucleotide within the consensus splice site. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at