rs778149316
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_015272.5(RPGRIP1L):c.1709_1710insA(p.Asp571GlyfsTer12) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000304 in 1,612,168 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )
Consequence
RPGRIP1L
NM_015272.5 frameshift
NM_015272.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.44
Genes affected
RPGRIP1L (HGNC:29168): (RPGRIP1 like) The protein encoded by this gene can localize to the basal body-centrosome complex or to primary cilia and centrosomes in ciliated cells. The encoded protein has been found to interact with nephrocystin-4. Defects in this gene are a cause of Joubert syndrome type 7 (JBTS7) and Meckel syndrome type 5 (MKS5). [provided by RefSeq, Jun 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 16-53652977-C-CT is Pathogenic according to our data. Variant chr16-53652977-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 188192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RPGRIP1L | NM_015272.5 | c.1709_1710insA | p.Asp571GlyfsTer12 | frameshift_variant | 15/27 | ENST00000647211.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RPGRIP1L | ENST00000647211.2 | c.1709_1710insA | p.Asp571GlyfsTer12 | frameshift_variant | 15/27 | NM_015272.5 |
Frequencies
GnomAD3 genomes ? AF: 0.000158 AC: 24AN: 152166Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000400 AC: 10AN: 250264Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135388
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GnomAD4 exome AF: 0.0000171 AC: 25AN: 1460002Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 726426
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GnomAD4 genome ? AF: 0.000158 AC: 24AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74340
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 11, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Aug 03, 2020 | - - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 22, 2023 | This sequence change creates a premature translational stop signal (p.Asp571Glyfs*12) in the RPGRIP1L gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RPGRIP1L are known to be pathogenic (PMID: 17558409). This variant is present in population databases (rs778149316, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with Joubert syndrome (PMID: 26092869). ClinVar contains an entry for this variant (Variation ID: 188192). For these reasons, this variant has been classified as Pathogenic. - |
Joubert syndrome 7 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | UW Hindbrain Malformation Research Program, University of Washington | Feb 23, 2015 | - - |
Meckel syndrome, type 5;C1969053:Joubert syndrome 7;C5436841:COACH syndrome 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 30, 2022 | - - |
Familial aplasia of the vermis Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
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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