rs199715125
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_031924.8(RSPH3):c.-198G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,611,082 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 1 hom. )
Consequence
RSPH3
NM_031924.8 5_prime_UTR
NM_031924.8 5_prime_UTR
Scores
19
Clinical Significance
Conservation
PhyloP100: -4.13
Genes affected
RSPH3 (HGNC:21054): (radial spoke head 3) The protein encoded by this gene acts as a protein kinase A anchoring protein. Mutations in this gene cause primary ciliary dyskinesia; a disorder characterized by defects of the axoneme in motile cilia and sperm flagella. The homolog of this gene was first identified in the blue-green algae Chlamydomonas as encoding a radial spoke protein that formed a structural component of motile cilia and flagella. Alternate splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Dec 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.02807337).
BS1
?
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000147 (215/1458910) while in subpopulation MID AF= 0.00139 (8/5750). AF 95% confidence interval is 0.000692. There are 1 homozygotes in gnomad4_exome. There are 113 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RSPH3 | NM_031924.8 | c.-198G>A | 5_prime_UTR_variant | 1/8 | ENST00000367069.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RSPH3 | ENST00000367069.7 | c.-198G>A | 5_prime_UTR_variant | 1/8 | 1 | NM_031924.8 | P1 | ||
RSPH3 | ENST00000449822.5 | c.-198G>A | 5_prime_UTR_variant | 1/6 | 2 | ||||
TAGAP-AS1 | ENST00000607391.5 | n.236+9176C>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.000125 AC: 19AN: 152172Hom.: 0 Cov.: 32
GnomAD3 genomes
?
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GnomAD3 exomes AF: 0.000136 AC: 34AN: 249198Hom.: 0 AF XY: 0.000126 AC XY: 17AN XY: 134634
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GnomAD4 exome AF: 0.000147 AC: 215AN: 1458910Hom.: 1 Cov.: 32 AF XY: 0.000156 AC XY: 113AN XY: 725288
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GnomAD4 genome ? AF: 0.000125 AC: 19AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10AN XY: 74342
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 19, 2022 | The c.229G>A (p.G77R) alteration is located in exon 1 (coding exon 1) of the RSPH3 gene. This alteration results from a G to A substitution at nucleotide position 229, causing the glycine (G) at amino acid position 77 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Primary ciliary dyskinesia 32 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 20, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 77 of the RSPH3 protein (p.Gly77Arg). This variant is present in population databases (rs199715125, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with RSPH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 475829). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
N
MutationTaster
Benign
N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Gain of methylation at G77 (P = 0.0328);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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