rs372634959
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001010892.3(RSPH4A):c.1976C>A(p.Pro659His) variant causes a missense change. The variant allele was found at a frequency of 0.0000267 in 1,612,174 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000028 ( 0 hom. )
Consequence
RSPH4A
NM_001010892.3 missense
NM_001010892.3 missense
Scores
8
6
5
Clinical Significance
Conservation
PhyloP100: 5.44
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 Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.841
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RSPH4A | NM_001010892.3 | c.1976C>A | p.Pro659His | missense_variant | 6/6 | ENST00000229554.10 | NP_001010892.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RSPH4A | ENST00000229554.10 | c.1976C>A | p.Pro659His | missense_variant | 6/6 | 1 | NM_001010892.3 | ENSP00000229554.5 | ||
RSPH4A | ENST00000368581.8 | c.*37C>A | 3_prime_UTR_variant | 5/5 | 1 | ENSP00000357570.4 | ||||
RSPH4A | ENST00000368580.4 | c.1235C>A | p.Pro412His | missense_variant | 5/5 | 5 | ENSP00000357569.4 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151862Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
2
AN:
151862
Hom.:
Cov.:
32
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:
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251302Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135806
GnomAD3 exomes
AF:
AC:
4
AN:
251302
Hom.:
AF XY:
AC XY:
3
AN XY:
135806
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000281 AC: 41AN: 1460312Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20AN XY: 726514
GnomAD4 exome
AF:
AC:
41
AN:
1460312
Hom.:
Cov.:
31
AF XY:
AC XY:
20
AN XY:
726514
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151862Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74146
GnomAD4 genome
AF:
AC:
2
AN:
151862
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74146
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
1
ExAC
AF:
AC:
2
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 17, 2022 | This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 659 of the RSPH4A protein (p.Pro659His). This variant is present in population databases (rs372634959, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of RSPH4A-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 525236). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RSPH4A protein function. 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
H;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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