NM_031924.8:c.894_897delTGAA
Variant summary
Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_031924.8(RSPH3):c.894_897delTGAA(p.Asn298LysfsTer19) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000702 in 1,425,274 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 7.0e-7 ( 0 hom. )
Consequence
RSPH3
NM_031924.8 frameshift
NM_031924.8 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.06
Publications
0 publications found
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]
RSPH3 Gene-Disease associations (from GenCC):
- primary ciliary dyskinesia 32Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- primary ciliary dyskinesiaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 7 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.289 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-158978308-CTTCA-C is Pathogenic according to our data. Variant chr6-158978308-CTTCA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 204501.Status of the report is no_assertion_criteria_provided, 0 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_031924.8. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| RSPH3 | MANE Select | c.894_897delTGAA | p.Asn298LysfsTer19 | frameshift | Exon 7 of 8 | NP_114130.4 | |||
| RSPH3 | c.1032_1035delTGAA | p.Asn344LysfsTer19 | frameshift | Exon 5 of 6 | NP_001333347.1 | Q86UC2-2 | |||
| RSPH3 | n.1531_1534delTGAA | non_coding_transcript_exon | Exon 7 of 9 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| RSPH3 | TSL:1 MANE Select | c.894_897delTGAA | p.Asn298LysfsTer19 | frameshift | Exon 7 of 8 | ENSP00000356036.1 | A0A0C4DFU3 | ||
| RSPH3 | c.726_729delTGAA | p.Asn242LysfsTer19 | frameshift | Exon 6 of 7 | ENSP00000554944.1 | ||||
| RSPH3 | TSL:2 | c.606_609delTGAA | p.Asn202LysfsTer19 | frameshift | Exon 5 of 6 | ENSP00000393195.1 | A0A0C4DG29 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 7.02e-7 AC: 1AN: 1425274Hom.: 0 AF XY: 0.00000141 AC XY: 1AN XY: 711392 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
1
AN:
1425274
Hom.:
AF XY:
AC XY:
1
AN XY:
711392
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
32786
American (AMR)
AF:
AC:
0
AN:
44312
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25834
East Asian (EAS)
AF:
AC:
0
AN:
39368
South Asian (SAS)
AF:
AC:
0
AN:
85234
European-Finnish (FIN)
AF:
AC:
0
AN:
52376
Middle Eastern (MID)
AF:
AC:
0
AN:
5604
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1080616
Other (OTH)
AF:
AC:
0
AN:
59144
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
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0
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1
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
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Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:no assertion criteria provided
Pathogenic
VUS
Benign
Condition
1
-
-
Primary ciliary dyskinesia 32 (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
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
Publications
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