rs397518456
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001010892.3(RSPH4A):c.1270del(p.Thr424GlnfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,048 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 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
RSPH4A
NM_001010892.3 frameshift
NM_001010892.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.121
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]
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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
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Very rare variant in population databases, with high coverage;
PP5
?
Variant 6-116627975-GA-G is Pathogenic according to our data. Variant chr6-116627975-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 66993.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-116627975-GA-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RSPH4A | NM_001010892.3 | c.1270del | p.Thr424GlnfsTer19 | frameshift_variant | 3/6 | ENST00000229554.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RSPH4A | ENST00000229554.10 | c.1270del | p.Thr424GlnfsTer19 | frameshift_variant | 3/6 | 1 | NM_001010892.3 | P1 | |
RSPH4A | ENST00000368581.8 | c.1270del | p.Thr424GlnfsTer19 | frameshift_variant | 3/5 | 1 | |||
RSPH4A | ENST00000368580.4 | c.922-1590del | intron_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152176Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251384Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135872
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11AN XY: 727238
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74336
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia 11 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 31, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 05, 2013 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at