chr6-43645100-T-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate
The NM_152732.5(RSPH9):c.2T>C(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000118 in 1,610,930 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: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000069 ( 0 hom. )
Consequence
RSPH9
NM_152732.5 start_lost
NM_152732.5 start_lost
Scores
8
5
2
Clinical Significance
Conservation
PhyloP100: 5.14
Genes affected
RSPH9 (HGNC:21057): (radial spoke head component 9) This gene encodes a protein thought to be a component of the radial spoke head in motile cilia and flagella. Mutations in this gene are associated with primary ciliary dyskinesia 12. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Jul 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_152732.5 (RSPH9) was described as [Pathogenic] in ClinVar as 2887444
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 6-43645100-T-C is Pathogenic according to our data. Variant chr6-43645100-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1297692.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-43645100-T-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RSPH9 | NM_152732.5 | c.2T>C | p.Met1? | start_lost | 1/5 | ENST00000372163.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RSPH9 | ENST00000372163.5 | c.2T>C | p.Met1? | start_lost | 1/5 | 1 | NM_152732.5 | P1 | |
RSPH9 | ENST00000372165.8 | c.2T>C | p.Met1? | start_lost | 1/6 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152196Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000328 AC: 8AN: 243710Hom.: 0 AF XY: 0.0000300 AC XY: 4AN XY: 133186
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GnomAD4 exome AF: 0.00000686 AC: 10AN: 1458734Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4AN XY: 725840
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GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152196Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8AN XY: 74348
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Primary ciliary dyskinesia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2023 | This sequence change affects the initiator methionine of the RSPH9 mRNA. The next in-frame methionine is located at codon 33. This variant is present in population databases (no rsID available, gnomAD 0.02%). Disruption of the initiator codon has been observed in individuals with primary ciliary dyskinesia (PMID: 23993197, 25789548; Invitae). ClinVar contains an entry for this variant (Variation ID: 1297692). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
0.93
.;P
Vest4
MutPred
Loss of stability (P = 0.001);Loss of stability (P = 0.001);
MVP
ClinPred
D
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