rs1554247978
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001010892.3(RSPH4A):c.11C>G(p.Ser4Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
RSPH4A
NM_001010892.3 stop_gained
NM_001010892.3 stop_gained
Scores
1
6
Clinical Significance
Conservation
PhyloP100: -0.0860
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 does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 37 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 6-116616634-C-G is Pathogenic according to our data. Variant chr6-116616634-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 525311.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RSPH4A | NM_001010892.3 | c.11C>G | p.Ser4Ter | stop_gained | 1/6 | ENST00000229554.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RSPH4A | ENST00000229554.10 | c.11C>G | p.Ser4Ter | stop_gained | 1/6 | 1 | NM_001010892.3 | P1 | |
RSPH4A | ENST00000368581.8 | c.11C>G | p.Ser4Ter | stop_gained | 1/5 | 1 | |||
RSPH4A | ENST00000368580.4 | c.11C>G | p.Ser4Ter | stop_gained | 1/5 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460670Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726546
GnomAD4 exome
AF:
AC:
1
AN:
1460670
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Cov.:
32
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AC XY:
1
AN XY:
726546
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
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 | Sep 27, 2017 | This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser4*) in the RSPH4A gene. It is expected to result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with RSPH4A-related disease. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in RSPH4A are known to be pathogenic (PMID: 19200523). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at