rs902750903
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001010892.3(RSPH4A):c.1707del(p.Glu570LysfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000394 in 152,126 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Consequence
RSPH4A
NM_001010892.3 frameshift
NM_001010892.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.11
Genes affected
RSPH4A (HGNC:21558): (radial spoke head component 4A) This gene encodes a protein that appears to be a component the radial spoke head, as determined by homology to similar proteins in the biflagellate alga Chlamydomonas reinhardtii and other ciliates. Radial spokes, which are regularly spaced along cilia, sperm, and flagella axonemes, consist of a thin 'stalk' and a bulbous 'head' that form a signal transduction scaffold between the central pair of microtubules and dynein. Mutations in this gene cause primary ciliary dyskinesia 1, a disease arising from dysmotility of motile cilia and sperm. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 6-116629609-GA-G is Pathogenic according to our data. Variant chr6-116629609-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 454522.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-116629609-GA-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RSPH4A | NM_001010892.3 | c.1707del | p.Glu570LysfsTer14 | frameshift_variant | 4/6 | ENST00000229554.10 | |
LOC124901386 | XR_007059721.1 | n.840del | non_coding_transcript_exon_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RSPH4A | ENST00000229554.10 | c.1707del | p.Glu570LysfsTer14 | frameshift_variant | 4/6 | 1 | NM_001010892.3 | P1 | |
RSPH4A | ENST00000368581.8 | c.1663-824del | intron_variant | 1 | |||||
RSPH4A | ENST00000368580.4 | c.966del | p.Glu323LysfsTer14 | frameshift_variant | 3/5 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152126Hom.: 0 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
6
AN:
152126
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152126Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74304
GnomAD4 genome
?
AF:
AC:
6
AN:
152126
Hom.:
Cov.:
33
AF XY:
AC XY:
3
AN XY:
74304
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 04, 2017 | This sequence change deletes 1 nucleotide from exon 4 of the RSPH4A mRNA (c.1707delA), causing a frameshift at codon 570. This creates a premature translational stop signal (p.Glu570Lysfs*14) and is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in RSPH4A are known to be pathogenic (PMID: 19200523). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at